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Abstract: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide, considered as a major worldwide healthcare problem. The pathophysiologic mechanisms that drive development and progression of this disease are complex and only poorly understood. Chronic inflammation observed in COPD is characterized by pro-inflammatory cytokine production and recruitment of several cell types to the lungs, including cells of the innate immune response, such as neutrophils and macrophages, as well as those of adaptive immune response, namely T and B cells. Components of the innate immune system have long been believed to be important in the development of COPD. More recent evidences also suggest involvement of the adaptive immune system in pathogenesis of this disease. Here we will review the literatures supporting the participation of T cells in the development of COPD. A better understanding of these complex immune processes will lead to new insights that could result in improved preventative and/or treatment strategies.
Keywords: COPD, T cells, adaptive immunity, inflammation, remodeling, network.
Chronic obstructive pulmonary disease (COPD) is characterized by expiratory airflow limitation that is not fully reversible, is usually progressive, and is associated with an abnormal intrapulmonary inflammatory response to noxious particles or gases. COPD is a leading cause of death worldwide, and one of the few diseases in which mortality rates continue to increase. Management of patients afflicted with COPD is often frustrating, and it is uncertain that any of the currently available treatments actually modify the natural history of the disease. While direct injury to airway and alveolar epithelium from chronic exposure to smoke is undoubtedly the primary risk factor for the development of COPD, the potential contributions of other disease mechanisms appear to be important. Individuals with COPD typically have at least a 10 pack-year history of tobacco smoking. However, only a minority of heavy smokers develop severe airflow abnormalities, suggesting that the disease is not solely attributable to smoke exposure. Furthermore, COPD often progresses, and intrapulmonary inflammation typically persists, despite removal of the inciting agent(s) with the cessation of smoking.
At the cellular level (fig.1), many biological processes characterize the development of COPD. The presence of intrapulmonary inflammation in COPD has been appreciated for many years, and accumulations and functions of activated macrophages and polymorphonuclear leukocytes (components of the innate immune system) have long been believed to be important in disease development  . More recent reports have suggested that the adaptive immune response also contributes to the pathophysiology of COPD. The cellular effectors of adaptive immunity are lymphocytes (both B- and T-cells), and the distinctive hallmarks of this system include antigen specificity, clonal expansions of antigen-activated lymphocytes, and the generation of immunologic memory.
A greater understanding of adaptive immune processes in COPD could perhaps lead to more effective disease interdictions, including elimination or eradication of the antigen(s), induction of tolerance to the antigen(s), manipulations of immunoregulatory mechanisms, or perhaps targeted depletion of specific disease-associated lymphocyte subpopulations. Here we will review some of the evidence supporting the hypothesis that T-cell responses are important in the pathogenesis of COPD (fig.2).
With its enormous surface area of approximately 150 m2, a volume of 350 Litres per hour of environmental air ventilated at rest, and highly fragile gaseous exchange surfaces, the respiratory tract poses a colossal challenge to the immune system. The presumed role of T cells in COPD was first suggested by histopathologic studies that found associations between disease severity and the extent of intrapulmonary lymphocyte infiltrates. FINKELSTEIN et al.  noted that lymphocytes and macrophages are the predominant cellular elements of the inflammatory infiltrates within airway walls of patients with COPD. These observations were extended by finding that numbers of CD8+ T cells in COPD lungs were directly related to the degree of airflow limitation  . Among many other analogous studies, the numbers of T cells in surgical lung resections of patients with emphysema were shown to be significantly increased, compared to findings in smokers without evidence of airflow obstruction or nonsmokers  . A recent comprehensive study of the morphometric changes seen in the small airways of COPD patients further noted the relatively unique presence of sub-epithelial lymphoid aggregates, described as bronchus associated lymphoid tissue (BALT), and the number of these BALT lesions was associated with the severity of airflow obstruction  . T cells can cause tissue injuries either by direct cytolytic activities or through the secretion of pro-inflammatory mediators that recruit and activate other immune cell types (e.g., phagocytic cells and B-cells)  . Pulmonary lymphocytes isolated from emphysematous lung tissue are frequently activated  and capable of secreting mediators that have been implicated in the pathogenesis of COPD  . T cells transit between inflammatory foci in organs and regional lymph nodes, and at least some proportion of these disease-specific lymphocytes also traffic within lymphatic and blood circulations  . Studies of peripheral blood T cells in patients with COPD have shown peripheral T cells (particularly CD8+) are more frequently activated and have increased productions of various mediators, and many of these T-cell abnormalities are highly correlated with disease severity  . Animal models of emphysema further corroborate the importance of T-cell responses in the development of COPD. The potential for activated T cells to cause lung injury in mice was evidenced after adoptive transfer of CD8+ T-cells with specificities for neoantigens that were expressed on alveolar epithelial cells  . CD8+ T cells were also recently shown to be critical for the induction of inflammation and tissue destruction in a murine model of smoke-induced emphysema  . In addition, adoptive transfers of syngeneic CD4+ lymphocytes that had been sensitized to endothelial cell antigens resulted in development of emphysema in naÃ¯ve rats, thus highlighting the potential for CD4+ T cell associated autoimmune disease processes in COPD  .
T cell-related airway inflammation in COPD
Based on the known physiologic behavior of T cells, the following may clarify the role of inflammation in COPD. NaÃ¯ve, non-antigen-activated T cells do not stay long in the lung, but, rather, they return to the circulation or die.  A role for T cells in causing a particular inflammatory disease is suspected largely because of the demonstration of increased T-cell numbers in the affected organ. For T cells to "home in" to the lungs (or to any organ) and proliferate, they need, first, to be activated by the recognition of an antigen and, second, to home in to the organ in which the antigen is being produced. Once in the lung, activated T cells could exert their effector functions (fig.3).
Cytotoxic T cells
CD8+ T cells are regarded as a hallmark cell of COPD, and are increased in both the central  and peripheral  airways of COPD patients. CD8+ T cells found within the airways are generally located within the submucosa and invading the epithelium  18. The majority of studies using patient-derived specimens seem to indicate that CD8+ lymphocytes appear to play a particularly important role in the development and/or progression of COPD  2021222324. Most (but not all) investigators have reported that COPD CD8+ lymphocytes secrete a Th1 predominant cytokine pattern that includes increased production of IFN-Î³, interferon-inducible protein-10 (IP-10), and monokine induced by interferon-gamma (MIG). In turn, these mediators can cause tissue destruction through the upregulation of matrix metalloproteinase (MMP) production by macrophages and other immune effectors  26. CD8+ T-lymphocytes can also mediate cell-death directly through the secretion of cytotoxic mediators (e.g., granzyme and perforins), as well as expression or secretion of Fas  28. Studies of CD8+ cytotoxic T-lymphocytes showed that they cause lysis of target cells by two mechanisms  : (1) membranolysis, in which secreted molecules, such as perforin and granzymes, form pores in the membrane of target cells; and (2) apoptosis, mediated through the triggering of apoptosis-inducing (Fas-like) surface molecules of the target cell.
Toll-like receptors (TLR), a key component of the innate immune system, sense foreign microbes via pathogen-associated molecular patterns. Although largely found on innate immune and structural cells  31, TLRs are also present on T cells, thereby contributing to the adaptive immune response  33. TLR activation results in a signal transduction cascade that acts through several pathways including NF-ÎºB and JNK, which subsequently bind to target DNA sequences.  This ultimately results in the production of inflammatory cytokines such as IL-1Î², IL-6, IL-8, TNF-Î± and IL-10, which can modulate inflammatory responses  3637. NADIGEL et al.  investigated the expression of TLR4 and TLR9 on CD8+ T cells, and reported for the first time increased expression of TLR4 and TLR9 on CD8+ T cells in lung tissue of COPD patients compared to control subjects. Moreover, data further demonstrated that cigarette smoke exposure induces TLR4 and TLR9 expression on CD8+ T cells, which results in increased production of cytokines, including IL-1Î², IL-6, IL-10, IL-12p70, TNF-Î± and IFN-Î³. Cigarette smoke activation of TLRs on CD8+ T cells and the resulting increased cytokine production represents a mechanism by which CD8+ T cells can contribute to the pathogenesis of COPD.
T helper cells
While the function of CD8+ T cells are often highlighted in COPD studies, the potential contributions of CD4+ T cells in the disease process also appear to be substantial. The number of CD4+ T cells in the lungs of smokers increased significantly after approximately 30 years of smoking, as did the CD8+ T cells, suggesting that the CD4+ T cell might be playing a role in the inflammatory process.  Although typically less extensive than CD8+ T-cell infiltrates, intraparenchymal CD4+ T cells are also present in abnormally increased numbers within emphysematous lungs  , particularly in proximity to BALT  .
CD4+ T cells are largely responsible for orchestrating downstream immune processes by the release of activating cytokines, and are important if not critical in focusing and amplifying inflammatory responses by other immune effector cells. CD4+ T cells have the potential to contribute to the inflammatory process via production of a variety of pro-inflammatory cytokines including TNF-Î± and granulocyte-macrophage colony-stimulating factor (GM-CSF), the Th1 agents IFN-Î³ and IL-2, and the Th2 agents IL-4, IL-5, and IL-6. CD4+ T cells are also required for the priming of CD8+ cytotoxic T-cell responses, for maintaining their memory, and for ensuring survival, suggesting that even low numbers of CD4+ T cells may be essential for the development of the CD8+ T-cell inflammatory infiltrate found in smokers. 
The facultative help provided by CD4+ T cells is also important for the activation and differentiation of antibody-elaborating B-cells. This "help" is especially critical for induction of B-cells to undergo isotype switch from production of IgM to more potent and avidly-binding IgG antibodies, particularly against protein antigens. FEGHALI-BOSTWICK et al. examined the possibility that CD4 T-cells could facilitate B-cell production of IgG autoantibodies in COPD patients. They found that âˆ¼70% of these patients had circulating IgG autoantibodies against epithelial cells, as ascertained by indirect immunofluorescence assays, compared to 10% among non-smoking controls and 13% of cigarette smokers without evidence of lung abnormalities  . An even more highly sensitive and specific immunoprecipitation assay showed that 34 out of 35 COPD patients (97%) had autoreactive antibodies against a variety of cellular self-antigens. Not only are circulating autoantibodies highly prevalent in COPD patients, but the immunoglobulins appeared likely to be pathogenic, as evidenced by findings of immune complex deposition and complement activation in surgically resected end-stage COPD lungs, and the evident ability of these autoantibodies to induce antibody dependent cell-mediated cytotoxicity (ADCC).
IL-17A, secreted by Th17 cells, induces airway epithelial cells to release IL-8 and granulocyte macrophage colony-stimulating factor (GM-CSF). GM-CSF stimulates neutrophils and macrophages to proliferate and undergo chemotaxis, and thus activates the inflammatory response in COPD. IL-17A can also induce the release of matrix metalloproteinase (MMP)-9, which is involved in emphysema  . It was previously found that the number of cells expressing IL-17A in the bronchial mucosa was significantly increased in COPD patients  .
Memory T cells
SULLIVAN et al.  reported a higher percentage of CD4+ and CD8+ T-cells expressing CD45R0 and a lower proportion expressing CD28 in the lung of patients with emphysema, as compared with in their own blood, and suggested that this was indicative of activated effector memory T-cells being actively recruited into the lungs of patients with emphysema. However, BARCELÓ et al.  interpretation of this same finding was different because, at variance with the previous investigation, control subjects were also studied. By doing so, BARCELÓ et al. found that the higher proportion of CD4+CD45R0+ and CD8+CD45R0+ T-cells (as well as the lower percentage of CD4+CD28+ or CD8+CD28+) reported in COPD also occurred in smokers with normal lung function and even in never-smokers. Therefore, these changes cannot be directly linked to the pathogenesis of COPD and probably represent the physiological homing of mature T-cells in the lungs as compared with the general pool of circulating T-lymphocytes. Furthermore, the inclusion of controls allowed the present study to compare BALF data between groups and to unravel some interesting differences. First, it was observed that patients with COPD showed higher CD8+CD45RA+ and lower CD8+CD45R0+ levels than smokers with normal lung function. The normal maturation-activation process of T-cells involves the sequential expression of CD45RA (naÃ¯ve T-cells), CD45R0 (mature T-cells) and, again, CD45RA (effector/cytotoxic T-cells)  . Therefore, the observation of a higher proportion of CD8+CD45RA+ T-cells in patients with COPD may indicate a final maturation-activation state of these cells (CD8+ cells expressing CD45RA and perforin) with a correspondingly higher potential for tissue injury  . However, the exact phenotype of these lymphocytes should be addressed in order to confirm the data.
AGUSTI et al.  showed a selective recruitment of memory CD4 cells into the lungs through lung and PBMC data, and supported a role for CD4 cells in any autoimmune processes that may be occurring in the lungs of smokers. SYMTH et al.  observed that the majority of CD4 cells in the BAL of COPD patients and smokers were memory cells (CD45R0) with increased activation (CD69). Memory CD4 cells are indicative of immune responses to chronic antigen stimulation. In contrast, BARCELÓ et al.  observed that the percentage of CD4+ T-cells expressing the maturation markers CD45RA or CD45R0 in BALF was not significantly different between groups, suggesting a different role for these T-cells in the pathogenesis of the disease, such as the modulation of the immune response by CD4+CD25+ Tregs discussed hereafter.
Regulatory T cells
In addition to the generally potent pro-inflammatory effects of CD4+ lymphocytes, a subset of these cells may also (and perhaps more favorably) influence the progression of immunologic diseases, including COPD, by acting to dampen the intensity of inflammatory cascades. Tregs constitute a small subpopulation of CD4+ T-cells expressing CD25, which have been recently identified as key immunomodulators in many chronic inflammatory and autoimmune disorders, including atherosclerosis and rheumatoid arthritis  545556.
Dysfunction of Tregs can lead to autoimmune diseases, allergy and chronic inflammatory diseases  5859. In patients with autoimmune diseases, reduced levels of circulating CD4+CD25+ T-cells are described, especially in individuals with juvenile idiopathic arthritis, psoriatic arthritis, hepatitis C, virus-associated mixed cryoglobulinaemia, autoimmune liver disease, systemic lupus erythematosus and Kawasaki disease  . Low levels of circulating CD4+CD25+ T-cells also correlate with a higher disease activity or poor prognosis. It has been proposed that downregulation of Treg cells may be caused by impaired proliferation of peripheral CD4+CD25+ T-cells, as observed in vitro. Thereby, the balance between pro-inflammatory and regulatory T-cells could be disturbed, leading to the breakdown of self-tolerance  6263. In recent years, several authors have described the presence of an autoimmune component in the pathogenesis of COPD. TARSEVICIENE-STEWART et al.  showed that rats immunized against endothelial cells developed emphysema. The disease might be passively transferred to naÃ¯ve rats by blood serum or CD4+ cells. The study suggested that this model provides a proof of principle that an autoimmune attack can cause alveolar destruction. A study by VAN DER STRATE et al.  examined lymphatic follicules that appear in patients' lungs with emphysema and found here B-cells with an oligoclonal, antigen-specific reaction. Similar follicles developed in smoking mice. The development was progressive with time and correlated with the increase in airspace enlargement. The hypothesis was that these B-cells contributed to the inflammatory process and/or the development and perpetuation of emphysema by producing antibodies against either tobacco smoke residues or extracellular matrix components. LEE et al.  suggested that emphysema could have an autoimmune component characterized by the presence of anti-elastin antibody and T-helper cell (Th) type 1 responses. Furthermore, anti-epithelial and tobacco anti-idiotypic antibodies have been observed in smoking patients with COPD  68. All these observations raise the question on the role of Treg cells in the pathogenesis of COPD.
Regulatory CD4+CD25+ T-cells in humans represent between 1% and 3% of total CD4+ T-cells and accumulate at tissue sites of antigen invasion where they exert site-localized immune suppression producing interleukin (IL)-10 and transforming growth factor (TGF)-Î²1  . Intracellular expression of FOXP3 is currently considered as the most specific marker for human Treg cells. Human FOXP3 is localized on the X chromosome encoding scurfin, which binds to the IL-2 promotor and the granulocyte-macrophage colony-stimulating factor enhancer, near the nuclear factor of activated T-cell (NFAT) sites. FOXP3 represses these genes, thus reducing IL-2 production by CD4+ T-cells  71. Although FOXP3 expression was primarily restricted to CD4+CD25+ cells, it was induced following activation of both CD4+ and CD8+ T-cell clones. The large majority of FOXP3-expressing regulatory T-cells is found within the major histocompatibility complex (MHC) class II restricted CD4+ helper T-cell population and express high levels of the interleukin-2 receptor alpha chain (CD25). Recent data indicate that FOXP3 gene expression can be induced also in CD25-T-cells under special conditions. These induced FOXP3-expressing cells also have a suppressive capacity, suggesting that a tight link exists between FOXP3 expression and a regulatory function  .
Tregs maintain the homeostasis of the immune system, avoiding the activation of undesirable responses to self- and nonself- antigens. After activation, Tregs suppress proliferation of CD4+ and CD8+ T-cells through cell contact-dependent mechanisms and secretion of cytokines, mostly IL-10. SYMTH et al.  suggested that chronic cigarette exposure resulted in increased Treg populations in the bronchoalveolar lavage (BAL) of COPD patients, but these cells were paradoxically believed to be functionally impaired. Conversely, LEE et al.  found decreased numbers of functionally intact Tregs in emphysematous lung tissue compared to healthy lungs. BARCELÓ et al.  found that those smokers who manage to preserve their lung function despite their habit showed a prominent upregulation of Tregs in BALF compared with never-smokers, whereas this response was blunted in smokers who had developed COPD. Given the array of immunoregulatory functions of Tregs, their upregulation in smokers with normal lung function may be interpreted as an attempt to regulate and minimize the inflammatory response elicited by tobacco smoking, whereas the failure of this mechanism in patients with COPD may contribute to the enhancement and/or disregulation of such an inflammatory response, thus contributing to the pathogenesis of the disease.
ROOS-ENGSTRAND et al.  found that the percentage of FOXP3+ was decreased in smokers compared to never-smokers among CD25 expressing helper T cells. The data suggest that a large proportion of CD4+CD25+ cells in smokers do not express FOXP3 and, thus, have not a regulatory T cell function. Compared to smokers and non-smokers, a decrease in the expression of FOXP3 has been found in the smaller airways in COPD, whereas FOXP3 expression was increased in large airways in both smokers and subjects with COPD  . Another study reported increased regulatory T cell numbers in lymphoid follicles and bronchial tissue in subjects with moderate COPD  . Within the lung tissue, regulatory T cells expressing FOXP3 seem to be more abundant in larger airways compared to smaller airways. However, the role for FOXP3 in regulating the immune defence in different regions of the lungs in smoking and COPD needs to be further elucidated.
Further investigations into the potential impact of Treg cells in the development of smoking related lung inflammation and injury are necessary, and could have considerable eventual importance for development of novel therapeutics.
Another important effector function of the T lymphocyte is the alteration of their microvascular environment. Under the influence of cytokines secreted by antigen-activated T cells or through contact-dependent signals, microvascular endothelial cells perform several functions that contribute to inflammation.  Vasodilatation increases local blood flow and the delivery of leukocytes to sites of inflammation via prostacyclin and nitric oxide. By the expression of new or increased levels of certain surface proteins, postcapillary venule endothelial cells become adhesive to leukocytes. Also, antigen-activated T cells cause endothelial cells to secrete chemokines such as IL-8 and monocyte chemotactic protein-1, which act on the leukocytes to promote their extravasation. Finally, cytokines or contact-dependent signals from activated T cells cause endothelial cells to undergo shape changes and basement membrane remodeling that favor the leakage of macromolecules and extravasation of cells.
T cell-associated airway remodeling
The chronic inflammatory immune process found in lung tissue repetitively damaged by tobacco smoke is also associated with a tissue repair and remodeling process that determines the ultimate pathologic phenotype of COPD. Their presence in the epithelial lining of the larger bronchi and their associated mucus glands produces the structural and functional changes associated with chronic bronchitis. When present in the smaller bronchi and bronchioles that become the major site of airway obstruction in COPD, this remodeling process results in occlusion of the lumen by inflammatory exudates containing mucus, thickening of the walls, and narrowing of the lumen of these airways  . In contrast, the extension of this inflammatory immune process to respiratory bronchioles and alveolar ducts and sacs is associated with emphysematous destruction rather than tissue proliferation seen in the conducting airway tissue  .
A multivariate analysis of the components of this inflammatory immune repair process conducted to determine the relationship between their presence in the small conducting airways and the decline in FEV1 has shown that more of the variance in FEV1 decline is explained by occlusion of the lumen and thickening of the airway wall than by either the extent (number of airways involved) or severity (accumulated volume of cells) in these airways of any of the inflammatory immune cells present in the tissue. These and other studies indicate that the remodeling process is a critical feature of the pathogenesis of the lesions that define the pathology of COPD, but much of the detail concerning the links between the innate and adaptive immune processes and peripheral lung remodeling remain to be worked out. 
TCR-Î³Î´ lymphocytes account for only 5% of the total T-cell subpopulation. However, they play a key role in mucosal homeostasis and the reparative response to tissue damage  . Furthermore, those Î³Î´ T-cells that coexpress the CD8 receptor have marked anti-inflammatory effects and contribute to suppress the cell-mediated immune response  .
Î³Î´ T-lymphocytes play an important role in tissue repair and mucosal homeostasis. Little is known about their potential role in COPD, except that they are an important component of tissue injury and remodeling. A previous study by RICHMOND et al.  reported increased Î³Î´ T-cell numbers in the bronchial glands of smokers compared with nonsmokers. Likewise MAJO et al.  found an increased percentage of Î³Î´ T-lymphocytes in the lung parenchyma of smokers. Finally, EKBERG-JANSSON et al.  evaluated Î³Î´ T-cells in peripheral blood and BAL samples, and also found a trend towards higher levels of Î³Î´ T-cells in smokers with normal lung function. PONS et al.  confirmed that, compared with never-smokers, smokers with normal lung function show a prominent upregulation of Î³Î´ T-lymphocytes in peripheral blood and, particularly, in BAL. It also shows that this occurs only in active smokers. Given the relevance of this T-lymphocyte subpopulation in tissue homeostasis, this observation is compatible with a physiological response aimed at protecting or repairing the lungs from the injury caused by current tobacco smoking. The specific molecular mechanisms leading to this upregulation of Î³Î´ T-lymphocytes in smokers are unknown. It is speculated that a direct stimulatory effect of some component(s) of smoke and/or the presence of the so-called ''danger signals'' produced by the damaged lung parenchyma may contribute to it.
In contrast, PONS et al. shows for the first time that COPD patients are unable to mount such a response. This can have two important pathogenic implications. First, it can jeopardize their capacity to repair the lung parenchyma, as illustrated in Î³Î´ T-lymphocytes knock-out mice that exhibit markedly delayed wound repair and re-epithelization due to the deficient production of keratinocyte growth factors and other cytokines  . Secondly, it may facilitate the perpetuation of the inflammatory response  . This is particularly relevant for Î³Î´ CD8+ positive T-cells which, at variance with Î³Î´ CD8- cells, can suppress the tissue damage mediated by effector T-cells.
In summary, the present study found that current smokers with preserved lung function showed a prominent upregulation of Î³Î´ and Î³Î´ CD8+ T-lymphocytes in bronchoalveolar lavage fluid, and that this response was blunted in smokers who had developed COPD. Whether this constitutes a previously unreported pathogenic factor that facilitates the development of COPD among certain smokers or, alternatively, whether it is a consequence of the disease process that contributes towards amplification of the inflammatory response caused by smoking and/or this prevents effective tissue repair, although these theories cannot be ascertained from the presented results. However, in both instances, the results of the present study pinpoint a novel, potentially relevant mechanism of disease that deserves further investigation.
Cytotoxic T cells
Increased CD8+ cell numbers are found in both the large and small airway walls in COPD and in peripheral airway smooth muscle.  Speculation has surrounded the role of CD8+ cells in emphysema. A key function of the CD8+ cell is to combat viruses either by cytolysis of infected cells or induction of apoptosis. If CD8+ cells destroy lung parenchyma, the mechanism is uncertain. They have, in theory, the potential to damage the lung interstitium directly via release of lytic substances such as perforin and granzyme. It was observed recently that CD8+ cells recovered from the sputum of COPD patients display higher levels of perforin expression and increased cytotoxic activity than CD8+ cells taken from control subjects.  Another possibility is that CD8+ cells induce structural cell apoptosis. Alveolar cell turnover does appear to increase in emphysema as increased numbers of alveolar epithelial and endothelial cells undergo both proliferation and apoptosis.  Moreover, an association has been observed between apoptosing cell numbers and CD8+ T cell numbers in the alveolar walls.  The possibility remains, however, that such associations are a secondary phenomenon. Given their potential suppressor function, the infiltrating CD8+ cells may actually serve to inhibit the inflammatory process.
Indirectly, overexpression of IFN-Î³ in transgenic mice results in apoptosis, inflammation, and emphysema  . Moreover, the IFN-Î³ and IFN-Î³-inducible protein-10 (IP-10) have been shown to be increased in CD8+ T cells from patients with emphysema; IP-10 was also shown to induce the production of MMP-12 in human alveolar macrophages  . MMP-12 degrades elastin, disrupting lung architecture leading to airspace enlargement. In addition, HOUGHTON et al. have recently shown that EFs, by-products of elastin destruction, are the major chemotactic factors responsible for macrophage accumulation and the subsequent development of experimental emphysema  . Humans with COPD have increased amounts of IP-10 and its receptor CXCR3  . Induction of IP-10 in CD8+ T cells and bronchiolar epithelium is thought to signal through CD8+ T cell CXCR3 to recruit T lymphocytes in COPD. Recently, it was shown that alveolar macrophages also express CXCR3 and that IP-10 signals through macrophage CXCR3 to produce MMP-12. In general, MMP-12 can only be detected in small amounts when subjecting concentrated BALF to zymography. This low-level expression, which likely requires close contact of macrophages with elastin within the interstitium, is consistent with the chronic nature of the injury observed in COPD.
T cell-associated networks
Gene Regulatory Network
COPD is characterized by chronic and progressive dyspnoea, cough and sputum production. T-cells may play a key role in the pathogenesis of COPD and chronic bronchitis. Activating naÃ¯ve T cells requires the presence of the antigen and co-stimulatory molecules B7-B7.1 (CD80) and B7.2 (CD86) on antigen-presenting cells. The receptor on the T cell for B7 is CD28. Activated T cells express an additional receptor, the cytotoxic T-lymphocyte antigen (CTLA) 4, which binds to B7 with a much higher affinity than CD28 and plays a potent role in downregulation of T-cell activation  . CTLA4 is induced following T-cell receptor (TCR)/CD28 stimulation; it arrests activated T-cells, thereby keeping them in an anergic state. Arrested T-cells exit the lymph nodes and enter the circulation  . Blocking CTLA4 can intensify T-cell responses and exacerbate autoimmune disease  ; CTLA4-deficient mice die by 3-4 weeks of age due to multi-organ lymphocytic infiltration and tissue destruction. CTLA4, which is located at chromosome 2q33, has been associated with several inflammatory diseases including asthma  . Therefore, CTLA4 is a candidate gene for COPD and/or chronic bronchitis because of its critical effect on inhibiting the activation of T-cells.
Genetic association between nine CTLA4 single nucleotide polymorphisms (SNPs) and chronic bronchitis was assessed in 606 pedigrees (1,896 individuals) from the International COPD Genetics Network (ICGN) population. ZHU et al. then replicated the associations in 342 COPD subjects with chronic bronchitis and 511 COPD subjects without chronic bronchitis from Bergen, Norway. Family-based association tests were used to analyze the ICGN cohort, and a logistic regression model was used for the Bergen cohort. It was concluded that six CTLA4 SNPs were significantly associated with chronic bronchitis in the ICGN cohort (0.0079fpf0.0432), with three being replicated with the same directionality of association in the Bergen cohort (0.0325fpf0.0408). One of these replicated SNPs (rs231775) encodes the Thr to Ala substitution at amino acid position 17. Haplotype analyses supported the results of single SNP analyses. CTLA4 is likely to be a genetic determinant of chronic bronchitis among COPD cases. 
T-lymphocytes play a key role in the pathogenesis of COPD and chronic bronchitis. CTLA4 is a crucial gene in the control of T-cell activation. ZHU et al. speculate that the CTLA4 polymorphisms may compromise the regulatory function of CTLA4, and that a weakened inhibitory function of CTLA4 could facilitate T-cell proliferation and differentiation, thus leading to airway inflammation and the symptoms of chronic cough and phlegm production that define chronic bronchitis. This would be in keeping with the recently proposed hypothesis of an abnormal acquired immune response in the pathogenesis of COPD  and would be supported by the following documented findings. CTLA4 controls a potentially damaging expansion of T-cells by arresting activated T-cells. However, this CTLA-mediated anergic check-point can be released by simultaneous stimulation of TCR/CD28 and the polarizing cytokines, interleukin (IL)-12 and IL-4, which lead to CD4+ T-cell differentiation towards T-helper cell (Th) type 1 and 2, respectively. Th1 CD4+ cells and cytotoxic T-cell-1 CD8+ cells are increased in COPD and chronic bronchitis. These cells secrete interferon (IFN)-Î³ and tumor necrosis factor (TNF)-Î±, which activate macrophages. Activated macrophages secrete IL-12, which in turn activates the transcription factor STAT4. There is an increased number of activated STAT4 and IFN-Î³+ cells in bronchial biopsies and bronchoalveolar lavage fluid in patients with COPD, and their increasing expression correlates with decreasing lung function.  If STAT4 signals in the lung overcome the inhibitory role of CTLA4  or the latter is genetically compromised, tissue inflammation and damage may ensue and COPD including chronic bronchitis may develop. It is of interest that one of the SNPs associated with chronic bronchitis (rs231775) is a nonsynonymous coding polymorphism, which results in a change of the amino acid at position 17 from Thr to Ala. This polymorphism is in the signal peptide and is absent from the mature protein. It could affect the efficiency of post-translational modifications other than cleavage, potentially resulting in inefficient processing in the endoplasmic reticulum, leading to reduced surface expression  . There are several reports showing the functional effect of this polymorphism on T-cell function. MÄURER et al.  examined the T-cell response from healthy donors homozygous for either A or G at nucleotide position 49 (amino acid position 17). They found that the G allele affected the CTLA4 downregulation of T-cell activation. In addition, blockade of CTLA4 ligation using soluble anti-CTLA4 monoclonal antibody did not augment proliferation as much in T-cells from G/G-expressing individuals as from A/A-expressing ones. Similar results have also been shown by SUN et al.  . All these studies show consistent results and it has to be noted that the association that identified with chronic bronchitis is with the G allele. Thus, this polymorphism might result in reduced expression of CTLA4, which could lead to the development of chronic bronchitis. However, ZHU et al. note that this variant may also be a marker for an un-genotyped variant in tight LD with this variant in the CTLA4 gene.
Immunomic Regulatory Network
The development of DNA microarray technology a decade ago led to the establishment of functional genomics as one of the most active and successful scientific disciplines today. With the ongoing development of immunomic microarray technology-a spatially addressable, large-scale technology for measurement of specific immunological response-the new challenge of functional immunomics is emerging, which bears similarities to but is also significantly different from functional genomics. Immunonic data has been successfully used to identify biological markers involved in autoimmune diseases, allergies, viral infections such as human immunodeficiency virus (HIV), influenza, diabetes, and responses to cancer vaccines. Based on the recent discovery of regulation mechanisms in T cell responses, BRAGA-NETO et al.  envision the use of immunomic microarrays as a tool for advances in systems biology of cellular immune responses, by means of immunomic regulatory network models.
Systems biology makes use of mathematical modeling in order to provide a theoretical core for biology, analogous to the way that mathematical theories provided that core for physics in the 20th century. Dynamical systems provide ''the natural language needed to describe the 'integrated behavior' of systems coordinating the actions of many elements'', and are also capable of displaying emerging self-order from massively disorganized complexity, which is believed to be a fundamental feature of life. In what follows is the notion of immunomic regulatory networks, a dynamical system model for immune regulation.
An important recent development in immunology has been the discovery of regulatory T cells. These T cells suppress immune responses, helping to stem runaway inflammatory processes and to avoid autoimmune disease. It is thought that this beneficial suppression activity can turn deleterious when it is taken advantage of by pathogens, leading to chronic and abnormal infectious processes. It has been observed that some regulatory T cells are not antigen-specific; these are called natural regulatory T cells. In addition, there exist regulatory T cells, both CD4+ and CD8+ that are antigen-specific and thus epitope-driven. Given the suppressive action of epitope-driven regulatory T cells in conjunction with the promoting activity of epitope-driven helper T cells, it follows that the immunological response to a given epitope may be suppressed or promoted by the immunological response to other epitopes. Thus the notion of regulatory networks arises as a fundamental concept in understanding the functioning of the immune system. In fact, most human diseases are the result of an unbalance in immune system homeostasis.
In the general case, each node of an immunomic regulatory network represents a combination of the epitope, the cytokine response measured, and the T cell population used as the target; in most cases, each node is in a one-to-one relationship with a single physical spot on an immunomic microarray experiment with a given T cell population. The edges between nodes represent putative regulatory relationships between the cells that respond to the respective epitopes. BRAGA-NETO et al. have proposed Boolean immunomic regulatory networks as a new mathematical model for immune system regulation. This is a dynamical system model, with parameters that can be estimated from immunomic microarray data.
Network of T Cell Receptor SignalingÂ : a qualitative Boolean network
Cellular decisions are determined by complex molecular interaction networks. Large-scale signaling networks are currently being reconstructed, but the kinetic parameters and quantitative data that would allow for dynamic modeling are still scarce. Therefore, computational studies based upon the structure of these networks are of great interest. A methodology relying on a logical formalism is applied to the functional analysis of the complex signaling network governing the activation of T cells via the T cell receptor, the CD4/CD8 co-receptors, and the accessory signaling receptor CD28. The large-scale Boolean model, which comprises 94 nodes and 123 interactions and is based upon well-established qualitative knowledge from primary T cells, reveals important structural features (e.g., feedback loops and network-wide dependencies) and recapitulates the global behavior of this network for an array of published data on T cell activation in wild-type and knock-out conditions. More importantly, the model predicted unexpected signaling events after antibody-mediated perturbation of CD28 and after genetic knockout of the kinase Fyn that were subsequently experimentally validated. It holds valuable potential in foreseeing the effects of drugs and network modifications. 
The importance of T cells for immune homeostasis is due to their ability to specifically recognize foreign, potentially dangerous agents and, subsequently, to initiate a specific immune response. T cell reactivity must be exquisitely regulated as either a decrease (which weakens the defense against pathogens with the consequence of immunodeficiency) or an increase (which can lead to autoimmune disorders and leukemia) can have severe consequences for the organism.
T cells detect foreign antigens by means of the TCR, which recognizes peptides only when presented upon MHC (Major Histocompatibility Complex) molecules. The peptides that are recognized by the TCR are typically derived from foreign (e.g., bacterial, viral) proteins and are generated by proteolytic cleavage within so-called antigen presenting cells (APCs). Binding of the TCR to peptide/MHC complexes and the additional binding of a different region of the MHC molecules by the co-receptors (CD4 in the case of T helper cells and CD8 in the case of cytotoxic T cells), together with co-stimulatory molecules such as CD28, initiates a plethora of signaling cascades within the T cell. These cascades give rise to a complex signaling network, which controls the activation of several transcription factors. These transcription factors, in turn, control the cell's fate, particularly whether the T cell becomes activated and proliferates or not  .
The logical model describing T cell receptor signaling, which comprises the main events and elements connecting the TCR, its co-receptors CD4/CD8, and the co-stimulatory molecule CD28, to the activation of key transcription factors in T cells such as AP-1, NFAT, and NFÎºB, all of which determine T cell activation and T cell function. In general, the model includes the following signaling steps emerging from the above receptors: the activation of the Src kinases Lck and Fyn, followed by the activation of the Syk-related protein tyrosine kinase ZAP70, and the subsequent assembly of the LAT signalosome, which in turn triggers activation of PLCÎ³1, calcium cascades, activation of RasGRP, and Grb2/SOS, leading to the activation of MAPKs. Additionally, it includes the activation of the PI3K/PKB pathway that regulates many aspects of cellular activation and differentiation, particularly survival. It is important to note that the model is also able to roughly predict the dynamics upon different stimuli and conditions.
Network of T Cell Receptor SignalingÂ : a continuous network
The understanding of regulatory and signaling networks has long been a core objective in Systems Biology. Knowledge about these networks is mainly of qualitative nature, which allows the construction of Boolean models, where the state of a component is either 'off' or 'on'. While often able to capture the essential behavior of a network, these models can never reproduce detailed time courses of concentration levels.
Naturally, Boolean models can neither describe continuous concentration levels nor realistic time scales. For this reason, they cannot be used to explain and predict the outcome of biological experiments that yield quantitative data. In this contribution, a practicable solution was presented and exemplified to this problem: a standardized method for accurately converting any Boolean model into a continuous model. When foreign antigens bind to their receptors, signaling cascades are triggered within the T-cell leading to an activation of several transcription factors. There are three inputs: the T-cell receptor TCR, the coreceptor CD4 and an input for CD45; as well as four outputs: the transcription factors CRE, AP1, NFkB and NFAT. The rephosphorylation of PAG-Csk by Fyn and cCbl mediated degradation are known to be slow processes compared to the other interactions. This is modeled by activating the feedback loops Fyn Æ PAG-Csk and ZAP-70 Æ cCbl only at a later stage. The continuous model is indeed a generalization of the Boolean model with richer dynamic properties. 
COPD is a complex syndrome with poorly understood pathophysiologic determinants. During the past few decades, the mortality rate of COPD has been steadily climbing and it is estimated that COPD will become the third leading cause of mortality by 2030  . Therefore, current research efforts are focusing on the cellular mechanisms of COPD in an attempt to identify potential therapeutic targets. The adaptive immune system appears to actively participate in disease development and progression. Better understanding of T-cell and other adaptive immune processes in COPD pathogenesis will eventually lead to the development of more selectively targeted and rational disease interventions. Given the awesome morbidity and mortality of COPD, and the generally limited effectiveness of currently available treatments, innovative approaches with greater therapeutic effectiveness are sorely needed, and would have profound clinical importance.