Critical For Innate And Adaptive Immunity Biology Essay

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IFN-γ, or type II interferon, is a cytokine that is critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. IFN-γ is an important activator of macrophages. Aberrant IFN-γ expression is associated with a number of autoinflammatory and autoimmune diseases. The importance of IFN-γ in the immune system stems in part from its ability to inhibit viral replication directly, and most importantly from its immunostimulatory and immunomodulatory effects. IFN-γ is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 Th1 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops. However, there is now evidence that other cells, such as B cells, NKT cells, and professional antigen-presenting cells (APCs) secrete IFN-_ (reviewed in refs. [5, 12-16]). IFN-_ production by professional APCs [monocyte/macrophage, dendritic cells (DCs)] acting locally may be important in cell self-activation and activation of nearby cells [12, 13]. IFN-_ secretion by NK cells and possibly professional APCs is likely to be important in early host defense against infection, whereas T lymphocytes become the major source of IFN-_ in the adaptive immune response [12, 17].

IFN-_ production is controlled by cytokines secreted by APCs, most notably interleukin (IL)-12 and IL-18. These cytokines serve as a bridge to link infection with IFN-_ production in the innate immune response [18-24]. Macrophage recognition of many pathogens induces secretion of IL-12 and chemokines [e.g., macrophage-inflammatory protein-1_ (MIP- 1_); ref. 25]. These chemokines attract NK cells to the site of inflammation, and IL-12 promotes IFN-_ synthesis in these cells [25, 26]. In macrophages, NK and T cells, the combination of IL-12 and IL-18 stimulation further increases IFN-_ production [20, 23, 24, 27, 28]. Negative regulators of IFN-_ production include IL-4, IL- 10, transforming growth factor-_, and glucocorticoids [17, 21, 27-29]. Given the complexity of IFN-_ regulation, it is not surprising that inbred mouse strains vary in their ability to secrete this cytokine; for example, T lymphocytes of C57BL/6

and C3H mice secrete significantly higher amounts of IFN-_ compared with the T lymphocytes of BALB/c and B10.D2 mice. Increased IFN-_ production in these strains is associated with greater resistance to bacteria and viruses [30-32]. Many excellent reviews on the regulation of IFN-_ production have

been published recently and the reader is referred to these forfurther information [11-13].

The primary sources of IFN-g are natural killer (NK) cells and natural killer T (NKT) cells, which are effectors of the innate immune response, and CD8 and CD4 Th1 effector T cells of the adaptive immune system. NK and NKT cells constitutively express IFN-g mRNA, which allows for rapid induction and secretion of IFN-g on infection. In contrast to NK and NKT cells, naive CD4 and CD8 T cells produce little IFN-g immediately following their initial activation. However, naive CD4 and CD8 T cells can gain the ability to efficiently transcribe the gene encoding IFN-g (IFNG in humans and Ifng in mice) over several days in a process that is dependent on their proliferation, differentiation, upregulation of IFN-g-promoting transcription factors, and remodeling of chromatin within the Ifng locus. Naive CD8 T cells are programmed to differentiate into IFN-g-producing cytotoxic effectors by default, whereas CD4 T cells can differentiate into a number of effector lineages, of which only Th1 CD4 effector T cells produce substantial amounts of IFN-g. The process of effector differentiation in CD4 T cells, and to a lesser extent in CD8 T cells, is influenced by the nature of the infecting pathogen and the cytokine milieu emanating from the innate immune system in response to the pathogen. These differences in priming conditions in turn can result in stable changes to the chromatin structure of the gene encoding IFN-g, either facilitating high-level expression in Th1 CD4 and CD8 effector T cells or silencing expression in other effector lineages.

It was believed earlier that IFN-γ is secreted by T helper cells (specifically, Th1 cells), cytotoxic T cells (TC cells) and NK cells only. But later studies showed that myeloid cells, dendritic cells and macrophage in particular, also secrets IFN-γ that is likely important for cell self activation during the onset of the infection. Also, IFN-γ is the only Type II interferon and it is serologicallydistinct from Type I interferons: it is acid-labile, while the type I variants are acid-stable.

IFN-γ has antiviral, immunoregulatory, and anti-tumor properties.[11] It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Among the effects are:

Promotes NK cell activity

Increase antigen presentation and lysosome activity of macrophages.

Activate inducible Nitric Oxide Synthase iNOS

Induces the production of IgG2a and IgG3 from activated plasma B cells

Promotes Th1 differentiation by upregulating the transcription factor T-bet, ultimately leading to cellular immunity: cytotoxic CD8+ T-cells and macrophage activity - while suppressing Th2 differentiation which would cause a humoral (antibody) response

Cause normal cells to increase expression of class I MHC molecules as well as class II MHC on antigen presenting cells-specifically through induction of antigen processing genes, including subunits of theimmunoproteasome (MECL1, LMP2, LMP7), as well as TAP and ERAAP in addition possibly to the direct upregulation of MHC heavy chains and B2-microglobulin itself

Promotes adhesion and binding required for leukocyte migration

Induces the expression of intrinsic defense factors-for example with respect to retroviruses, relevant genes include TRIM5alpha, APOBEC, and Tetherin, representing directly antiviral effects

IFN-γ is the primary cytokine which defines Th1 cells: Th1 cells secrete IFN-γ, which in turn causes more undifferentiated CD4+ cells (Th0 cells) to differentiate into Th1 cells, representing a positive feedback loop-while suppressing Th2 cell differentiation. (Equivalent defining cytokines for other cells include IL-4 for Th2 cells and IL-17 for Th17 cells.)

NK cells and CD8+ cytotoxic T cells also produce IFN-γ. IFN-γ suppresses osteoclast formation by rapidly degrading the RANK adaptor protein TRAF6 in the RANK-RANKLsignaling pathway, which otherwise stimulates the production of NF-κB.

IFN-ƒ£€ production is characterized as the hallmark of the Th1 phenotype and IFN-ƒ£€ has been shown to downregulate the generation of IL-4- and IL-10-producing Th2 T cells (reviewed in Szabo et al. 2003). Interestingly, IFN-ƒ£€ has been shown to enhance Th2 polarization and the survival of IL-4 producing cells if present during the initial T cell priming (Bocek et al. 2004). Most

recently IFN-ƒ£€ has been shown to inhibit the development of a new subset of T cells (Harrington et al. 2005), characterized by their ability to produce IL-17 (Bettelli et al. 2006; Harrington et al. 2005) . These cells play an important role in the development of a number of autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE) (Bocek et al. 2004). The

inhibition of their development by IFN-ƒ£€ begins to shed new light on the role of IFN-ƒ£€ in the development and progression of these diseases. There is also evidence that IFN-ƒ£€ can control the generation and activation of CD4 + /CD25 + regulatory T cells (Tregs). Tregs suppress a wide variety of immune responses and induce immune tolerance (see review Maloy and Powrie 2001) . Furthermore, a recent report demonstrated that pretreatment of mice with IFN-ƒ£€ prevented the development of Tregs reactive to immunized self antigens (Nishikawa et al. 2005). Surprisingly, Treg formation appears to be normal in ifng-/- and ifngR -/- mice, indicating that it is not required for Treg development (Kelchtermans et al. 2005; Sawitzki et al. 2005). Furthermore, Tregs can themselves produce IFN-ƒ£€ and this may trigger apoptosis in naïve and/or Th2 effector T cells (Dalton et al. 2000; Rafaeli et al. 2002), thus indicating that IFN-ƒ£€ may have a more generalized role in regulating host immunosuppression. These new findings, taken together with the classical roles of IFN-ƒ£€ in the pro-inflammatory response, demonstrate the widespread role of IFN-ƒ£€ in regulating the host immune response. The role of IFN-ƒ£€ in the host immune response to cancer has recently been reevaluated by Robert Schreiber's laboratory (Dunn et al. 2005). This laboratory has found that the tumor response to IFN-ƒ£€ is critical for an effective host response, as they demonstrated that in mice deficient in the IFN-ƒ£€ response (e.g., Stat1-/- or ifngR1-/- mice), there was a higher incidence of chemicallyinduced and spontaneous tumors. Insensitivity to IFN-ƒ£€ at the level of the tumor was a major factor contributing to the increased tumor incidence, as

IFN-ƒ£€ is required to increase tumor recognition by inducing MHC class 1 antigen processing and presentation pathway. A more thorough description of the role of IFN-ƒ£€ in the host response to tumor challenge and development can be found elsewhere (Dunn et al. 2005).