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T Cells Born: Like B cells, the T cells are also born in the bone marrow, originating from haematopoietic stem cells (HSC's). These are stem cells that give rise to the blood type molecules/cells. The T lymphocyte is a type of white blood cell. There are fixed numbers of HSC's in a tissue with a fixed behaviour. The stem cells are self renewal, meaning that they divide, keeping a copy in its original place and differentiating the other. There are 3 types of progenitors: multipotent (differentiation of many cells), oligopotent (differentiation of few cells) and unipotent (differentiation of a single cell). T cells are
thought to be derived from the oligopotent progenitors to produce immature thymocytes (produce T lymphocytes).
Figure 1 The eight major hematopoietic lineages generated by self-renewing multipotential stem cells.
T cells migrate and mature:
Immature T cells then leave the Bone marrow and migrate towards the thymus gland, where a positive or negative selection of cells takes place. The positive selection is when the "double positive" T cell is able to interact with the MHC molecule "self" antigen (if bound too weakly, they will undergo apoptosis); those able to interact are given the right to migrate into the deeper layer of thymic cortex and medulla where they are presented with another MHC molecule such as antigen presenting cells. Those that are able to interact are removed and undergo apoptosis. The remaining T cells leave the thymus as mature T cells. In negative selection, T thymocytes are presented with MHC presenting "self" peptides. Those able to interact strongly undergo apoptosis, those that survive, follow the path of the positively selected T lymphocytes (enter the cortex and medulla) and leave the thymus as mature T lymphocytes.
Antigen presenting cells (APC) are those cells that show antigens on their cell membranes that are recognised by lymphocytes TCR. B cells, macrophages, B lymphocytes and dendritic cells are examples of APC's. They have two types of behaviour: 1) present MHC class II and 2) produce cytokines that activate T helper cells.
MHC molecules are found in the surface of APC's and have multiple loci with large complexes. Theses loci produce 2 types of MHC classes: MHC class I and MHC class II; both of which have a cleft to which an antigenic peptides fits and binds. The peptide is now presented on the surface of APC's for TCR's to interact with.
T cells involved in regulatory activity
The three types of major T cells; all T cells interact with a specific type of glycoprotein (either CD4+, CD8+).
T Helper (TH) Cells:
Naive TH cells are activated by dendritic cells. TH differentiates into two types of cells: Effector cells and memory cells after activation (interaction with antigen-MHC complex). T cells become big, enter the cell cycle, divides to produce many T cells as well as Interleukin receptors (IL).
Effector cells help activate B cells, produce cytokines and carry out cytotoxic killing of cells by secreting cytotoxic chemicals. Their life span is very short (from a few days to a few weeks). There are 2 sub populations of effector cells: TH1 subset; have cell mediated functions (i.e. activation of TC). They secrete IL-2, IFN- Î³ and TNF-Î² as their cytokine chemicals. These chemicals are distinct from the 2nd subset of effector cells, the TH2 subset that secrete the following cytokines: IL-4, IL-5, IL-6 and IL-10. The second subset helps activate B cells.
Memory cells show antigens from which the effector T cells have reacted with. They have a long life span (years). Both memory and effector cells can derive from each other. Mature T cells show a specific CD4+ protein on their surface membrane that recognises and interacts with APC with specific MHC class II. Interaction involves secreting cytokines that produces different immune responses (metabolic transform), i.e. the induction of cytotoxic T cells to produce cytotoxic T lymphocytes (CTL's) that show properties of cell killing.
There are 4 types of T helper cells:
Th1: their main role is to control the activity f intracellular pathogens and produce help cytotoxic T cells with releasing pro-inflammatory cytokines (IFN-Î³, IL-2 and lymphotoxin-Î± (LTÎ±)).
Th2: Help B cell activity by producing immunoglobulin E (IgE) antibodies that is stimulated by the secretion cytokine IL-4.
Tfh (follicular helper T cells): Help B cell development into plasma cells.
Th17: protect the linings of internal organs and the skin from pathogens. They produce cytokine IL-17A that induces autoimmunity against tissue damage.
T cells are mainly responsible in activating and instructing other cells involved in the immune system aswell as determining the type of antibody switching in B cells, and the activation cytotoxic T cells.
Cytotoxic T cells (TC):
Cytotoxic T cells express TCR on their cell membranes that recognise antigen CD8+ on MHC class I molecule (MHC class I are shown by all nucleated cells). As discussed, TH cells induce TC cells to produce CTL; CTL's posses CD8+ proteins and TCR's that recognise proteins in the MHC class I cleft and with the help of TH cells producing IL-21, they kill the cell. There are two ways in which TC cell induce apoptosis: When TC cells are activated; they will release granulysin (induce apoptosis), granzymes (serine protease) and Perforin (aqueous channels). Once the TC interacts with infected cell, it will release perforin that will produce holes in the plasma membrane of host cell. This hole allows granzymes to be passed through, which cleaves and destroys residues inside the membrane of host cell. Finally granulysin is released into the cell that induces apoptosis of the cell. The resultant is cell death. The second way to induce apoptosis is that when TC cell is activated it will present a transmembrane protein known as FAS ligand from the TNF family (Tumor necrosis factor) that binds to its receptor (forming FAS-FAS interaction) on host cell, apoptosis is induced.
Many TCL may die after apoptosis, but a few become memory cells and have a long life span.
T regulatory (TREG) cells:
Also known as Suppressor T cells. It was previously thought that suppressor T cells provide their function using an "antigen nonspecific mechanisms" but this mechanism was rejected due to the findings of O'Garra (2004) when it was reviled that I-J, a restriction element was not found on the MHC locus and clones of the T cells lack TCR's.
TREG now-days follow an antigen specific activation pathway in order to activate, but their activity is entirely carried out through antigen-independent mechanisms.
Unlike cytotoxic T cells and T helper cells, TREG is selected rather differently in the thymus at the stage of maturation. We said that a weak bonding of T cell and MHC produces effector cells whereas a strong bonding will result in apoptosis. TREG requires a medium bonding with the MHC in order to be selected. TREG cells are delayed by a 3 weeks before maturation and require the stimulation of CD28+ protein.
There are 2 types of TREG cells: 1) Naturally occurring T regulatory cells and 2) IL-10 secreting cells.
TREG suppress the immune responses by identifying "self" peptides and suppressing the role of other T cells, thereby maintains homeostasis of the immune system and tolerance to "self" antigens this will prevent the body from achieving autoimmunity and immunopathology associated diseases.
Naturally occuring TREG's have CD4+ and CD25+ molecules (the chain of IL-2), glycocorticoid-induced tumor necrosis factor (TNF), and the CTLA-4 protein (cytotoxic T lymphocyte associated antigen 4). Natural TREG cells are mainly involved in the prevention and control of the autoimmune diseases; more specifically, they control the innate (IL-10 dependant) and adaptive immune systems. These cells are responsible for the suppression of naive T cells during proliferation by transduction of CD4+ T cells as a consequence of small production of IL-2 and IL-4, and the number of CD4+ and CD8+ T lymphocytes produced after proliferation. TREG expresses Foxp3 as a transcription factor that may suppress some cells and enhance others by programming the developmental stages and their functions. It is also responsible for the size of the compartment of CD8+ T cells. A mutation in this transcription factor gene results in no TREG cells in the body; however forced expression of this gene in a T cell that's not a regulatory T cell, induces the cell to develop into a regulatory T cell. Foxp3 gene can also be induced for new therapeutic treatments against transplantation tolerance, by "antigen-specific peripheral T lymphocyte" mechanism.
There is IL-2 complex and the TCR receptor on its membrane. TCR is activated in two ways: it will bind to MHC class II, or interacts with co-stimulation B7 molecule.
Either way, if TCR is activated (CTLA-4 binds with B7 molecule on host cell), it will produce large quantities of IL-10; by doing this, TREG will consequently inhibit the action of Th1 (cell-mediated immunity), Th2 (antibody production), Th17 (protection/autoimmunity) and CTL (cell killing). Although TREG cells regulate Th1 and Th2 cells, they in turn, also play a role in regulating immune responses by producing specific cytokines.
TREG IL- 10 cells produce IL-10 and Transforming growth factor (TGF-) cytokine and express CD25+ molecule. IL-10 and TGF- both act as mediators in suppression of TREG in autoimmunity and allergic pathology conditions. TREG IL-10 also suppresses the proliferation that is IL-10 dependant, and the process of expansion of naÃ¯ve T cells. These functions require the right environmental conditions such as cell-cell contact by TGF- complex. This process is called "cell-contact-mediated suppression".
Induction TREG IL-10 cells can be achieved by providing it with antigenic-peptides of MBP's (myelin basic proteins) in a repeatedly manner. By doing this, these T cells are capable of inhibiting the proliferation of MBP-specific naÃ¯ve T cells. Two major roles IL-10 carries out is inhibiting the function of APC cells and the pro-inflammatory cytokine producing cells.
IL-10 TREG cells also inhibit the proliferation and the size expansion of naturally occurring TREG cells.
Cells that produce IL-10 are Th1, Th2, IL-10 TREG cells, and APC's, all of which can play a role in regulating immune response and the limitation and control of immunopathology.
Both types of TREG will have a major role in regulating proliferation by using their own type of mechanism; however the two types of TREG cells are independent of each other, but a correlation between the two has been established; that is IL-10 expression of IL-10 TREG cell mirrors the significant decrease in IL2 expression of naturally occurring TREG, and that there is no IL-2 expression in Foxp3 TREG cells. More so, Foxp3 is suggested to be a "negative modulator" towards IL-2 transcription.
Inflammation reduction is achieved by the mechanism of both TREG cells through either IL-10 dependant or TGF- dependant mechanisms.
It is therefore shown that IL-10 is the main character in regulating all types of T cells, although some T cells produce IL-10.