Immune system does not attack the body’s own organs as it is tolerant to it. If it was not we would get AUTOIMMUNE DISEASE such as diabetes multiple sclerosis and rheumatoid arthritis. T and Dendritic cells play a major role in the adaptive immune response. Each T cell has its own individual T cell receptor due to the rearrangement of genes giving the adaptive immune response the power to recognise almost anything that can infect us. As the rearrangement of genes is a random process the T cells could by chance recognise parts of our own organs so a mechanism must be in place to stop T and B cells from attacking our own organs.
The CLONAL SELECTION HYPOTHESIS states that each T cell bears a single receptor with UNIQUE specificity and if it recognises an antigen MHC complex it will bind with high affinity to the antigen leading to activation of the T cell generating a clone of effector T cells and memory cells. Each activated T cell bears the receptor of identical specificity to the parent cell.
Unlike the ADAPTIVE immune response the INNATE immune response has a limited number and diversity of antigen receptors. These include pattern recognition receptors such as the Toll like receptors. The ligands for these receptors are repeating structures found on pathogens. They recognise broad pathogen patterns in groups of bacteria eg – cell wall on bacterial cells not present on host cells. These cells only distinguish self from non self cells and do not have the property of unique specificity that the adaptive cells do when recognise pathogens. For this reason self reactivity never occurs in the innate immune response and so it has no need to maintain self tolerance.
The adaptive immune response however has an enormous diversity of antigen receptors and the ligands it recognises are equally diverse and so it can distinguish between individual pathogens. So self reactivity is a major problem and tolerance is essential. There are two mechanisms of T cell tolerance. These are CENTRAL and PERIPHERAL tolerance. Central tolerance involves the deletion of self-reactive T cells in the thymus. Tolerance is induced as the T cells are being made. B cells are made tolerant whilst maturing in the bone marrow. But this system is not perfect and self reactive T cells may escape and be let out into the periphery and respond to self antigens. Peripheral tolerance uses mechanisms of INDIFFERENCE, DELETION AND REGULATORY T CELLS to control this problem.
The thymus is split into the outer cortex and inner medulla. Blood vessels enter at the boundary with progenitor cells from bone marrow and then become mature T cells. Become DOUBLE NEGATIVE THYMOCYTES and massive expansion follows into double positive cells expressing cd4+ AND cd8+ each having a unique TCR. Good proportion will recognise self antigens. They enter the medulla and lose either the cd8+ or cd4+ adhesion molecules to become one or the other. These are the mature T cells ready to leave the thymus and respond to infection. Before this there is a selection step whereby anything self reactive is first deleted. This is through the use of ANTIGEN PRESENTING CELLS in the thymus that fall into 3 CLASSES. These are the CORTICAL EPITHELIAL CELLS, MEDULLARY EPITHELIAL CELLS and THYMIC DENDRITIC CELLS. They are all capable of antigen presentation via MHC and all present SELF antigens. If the self antigen is recognised by any of the T cells the thymus ensures these are destroyed. cd4+ cells recognise antigens presented on MHC class 2 whilst cd8+ cells recognise antigens presented on MHC class-I cells. The T cell arrives at the junction with the APC containing self peptide and if it doesn’t recognise it at all there is no affinity between them and the T cell dies by negelect.(Not given any growth factors so it withers away as it is not useful) This is because it must be capable of at least recognising the MHC molecules. There could possibly have been a problem in the T-cell rearrangement process. If a T cell receptor recognise the self antigen and the MHC very well and there is a strong affinity and interaction the T-cell is likely to have perfect recognition of the self antigen and apoptosis takes place and programmed cell death occurs.(NEGATIVE SELECTION) The T cell is removed immediately. However if the interaction between the two is not very strong but there is a medium affinity it is likely that the MHC complex is being recognised and not the self peptide in which case it must recognise a different peptide that is foreign so the cell is not destroyed. It is allowed to survive and develop into cd4+ or cd8+ T-cells (POSITIVE SELECTION). Cortex is responsible for positive selection whereas negative selection occurs in the medulla. So the cortical epithelial cells drive positive selection displaying a range of self antigens normally found in epithelial cells. The thymic dendritic cells derived from the bone marrow display self-antigens from other cells of the body and drive negative selection. Medullary epithelial cells also drive negative selection and display a range of self-antigens from epithelial cells and organ or tissue specific antigens. So, medullary epithelial cells are responsible for the majority of negative selection.
Genes along the chromosomes for normal epithelial cells have epithelial cell specific genes turned on. Other genes eg – liver specific etc turned off as they are not needed. But all these genes are turned on in the medullary epithelial cells. Eg insulin, liver enzymes etc. These proteins can be presented by medullary epithelial cells. Special transcription factor controls this process – AIRE. It can turn on a whole host of what are normally tissue specific genes in the thymus. It regulates the presentation of peripheral tissue self-antigens on thymic medullary epithelial cells. It has been shown that mice lacking AIRE are more susceptible to multi-organ autoimmune diseases.
Once mature immunocompetenet T cells are produced they travel to the lymph nodes. (Naïve T cells) If they leave they normally travel to another lymph node and so stay on a very defined path and do not travel to tissues. This cycling is only changed when they are activated. This is a mechanism of INDIFFERENCE. It is the restricted migration of the naïve cells which only stay in lymph nodes or in circulation to another one. They also have a low precursor frequency expanding only when necessary helping to limit unwanted interactions. Due to the selection process in the thymus any cells that did pass through to the lymph nodes should have a low affinity for self antigens. It may have only escaped because it was on the border of recognising self antigen quite well, so it could be positively selected but not well enough to be negatively selected against.
Deletion or PROPRIOCIDAL regulation:
This tends to happen to T cells which recognise something extremely common (chronic/high dose of antigen) in the body. So it is activated continuously because it may be present in the lymph node or circulation. There is immediate activation because of the strong interactions which overrides all normal processes such as the presentation through Dendritic cells etc. There is massive activation and IL-2 production occurs. However because of such strong activations, the IL-2 that cells produce needed for expansion run out (IL-2 may be exhausted) and cell dies because it cannot sustain such massive activation and expansion. The cells die by apoptosis often mediated by Fas.
Regulatory T cells
These cells have an active function in dampening down self reactive immune responses. There are two types: NATURAL and INDUCIBLE. Natural self-antigen reactive cd4+cd25+ regulatory T cells develop in the thymus then enter peripheral tissues suppressing the activation of other self reactive T cells. Inducible cd4+ regulatory T cells which secrete IL-10 and TGF-beta are generated from naïve T cells in the periphery after encounter with antigen presented by DCs with the activation status distinct from those DCs promoting differentiation of Th1 or Th2 cells. There is also evidence for immunosuppressive functions of cd8+ regulatory T cells secreting IL-10. Antigen-activated cd8+ gamma delta T cells can prevent insulin-dependent diabetes in mice. NKT cells can secrete regulatory cytokines including IL-10.
Natural regulatory T cells express the surface marker cd25 and the transcriptional repressor FOXP3. They mature and migrate from the thymus. (5-10% of peripheral T cells in mice). Other populations of antigen specific regulatory T cells can be induced from cd4+cd25- or cd8+cd25- T cells in the periphery under the influence of semi-mature DCs, IL-10, TGF-beta and IFN gamma. The inducible populations of regulatory T cells include distinct subtypes of cd4+ T cells. These are T regulatory 1 cells that secrete large levels of IL-10, T helper 3 cells secreting high levels of TGF-beta and a subtype of cd8+ regulatory T cells secreting IL-10.
There is convincing evidence that self-antigen-reactive T cells that cause autoimmune diseases can be controlled through active suppression by natural regulatory T cells which is continuously produced in the thymus as functionally mature T cell populations with immunosuppressive activity.
Mechanism of suppressive function:
Suppressive functions are mediated through the secretion of immunosuppressive cytokines or cell-cell contact. cd4+cd25+foxp3+ natural regulatory T cells function through cell-cell contact. They express cytotoxic T lymphocyte antigen 4 (CTLA4) which interacts with cd80 or cd86 on the surface of APCs. Interaction delivers a negative signal for T cell activation. There is evidence that secreted or on cell surface is TGF-beta or IL-10 may also have a role in suppression.
Treg1, Treg3 (inducible populatiosn of T regulatory cells) and cd8+ regulatory T cells secrete IL-10 and/or TGF-beta. These immunosuppressive cytokines INHIBIT the proliferation of cytokine production by effector T cells including(Th1, Th2,cd8+ cytotoxic t lymphocytes) either directly or through inhibitory influence on the maturation and activation of APCs. They also down regulate the production of MHC class II molecules and co stimulatory molecules.