Immune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It is induced by prior exposure of that antigen. Immunological tolerance is a state of unresponsiveness of an individual to a particular antigen. The antigen which causes the tolerance is called tolerogen. Tolerance can be either natural or induced. Natural tolerance is unresponsiveness to self antigens whereas induced tolerance is the tolerance to external antigens can be created by manipulating the immune system.
Immunological tolerance is not a failure of immune system to recognize antigen, it is an active response to particular type of epitope of an antigen and it is just as specific as an immune response. Both B and T cells can be made tolerant, but it is more important to tolerize T cells than B cells because B cells cannot produce antibodies against many antigens without the help of T cells.Tolerance can also be differentiated into central tolerance and peripheral tolerance. Central tolerance is the process of eliminating any developing T cells or B cells that react with self antigens. It occurs in primary lymphoid organs such as thymus and bone marrow. Through elimination of self reactive lymphocytes, tolerance ensures that the immune system does not attack self peptides.
These cells are destroyed after they expressed receptors for self antigens and before they develop into fully immuncompetant lymphocytes. Deletion of autoreactive cells at an early stage in their development has been termed clonal deletion. In early fetal life, autoreactive cells that are part of the developing immune system are deleted when exposed to self antigens.
New immunocompetent cells are generated throughout life and these must be continuously deleted or inactivated.B cells showing high affinity for self cells can undergo clonal deletion within the bone marrow. This occurs after the assembly of functional B cell receptors (BCR). Autoreactive B cells may undergo receptor editing i.e. the autoreactive B cell changes specificity by gene rearrangement and develops a new BCR that does not react with self. This process gives the B cell a chance for BCR editing before it receives signals for programmed cell death (apoptosis) or may become anergic.
It is possible for B cells with high affinity to self to go undeleted because they require activation signals and stimulation from self reactive T cells. Such T cells are often removed through clonal deletion, leaving self reactive B cells unstimulated and unactivated. These B cells do not pose threat even in the periphery, because they cannot be activated without stimulation from self reactive T cells. Properly functioning BCR recognize non self antigens.T cell central tolerance occurs in thymus. 2% – 5% of T cells develop self reactive receptors that will undergo positive and negative selection. Many of these autoreactive cells undergo negative selection by clonal deletion. T cells showing high affinity for self MHC/peptide complexes will undergo clonal deletion in the thymus.
Thymic dendritic cells and macrophage are responsible for sending apoptotic signals to self reactive T cells in the thymic cortex. T cells also have the chance to undergo clonal deletion within the thymic medulla if they express high affinity for self MHC/peptide complexes. Positive selection occurs in the thymic cortex whereas negative selection occurs in the medulla through clonal deletion. In medulla epithelial cells are responsible for clonal deletion. These medullary epithelial cells can express an autoimmune regulatory (AIRE) that allow these cells to present proteins to T cells.
These proteins are specific to other parts of the body. This helps in the elimination of autoreactive T cells that recognize any of those proteins. T cells that do not bind to self antigen but can recognize antigen/MHC complexes, and are either CD4+ or CD8+, migrate to secondary lymphoid organs as mature naive T cells.However, not all antigens to which T cells need to be tolerant are expressed in the thymus, and thus central tolerance mechanisms are not sufficient alone. There are additional tolerance mechanisms exist that restrain the numbers and function of T cells that are reactive to developmental or food antigens, which are not expressed in the thymus. These mechanisms are referred to as peripheral tolerance.Peripheral tolerance mechanism acts on mature lymphocytes that left the primary lymphoid organs. As all the genes are not expressed in thymus so developing T cells cannot be exposed to all self antigens.
Therefore, additional mechanisms are necessary for tolerizing autoreactive mature T cells. Mechanisms of peripheral tolerance for B cells are also necessary because after stimulation with antigen B cells expand and undergo somatic mutation and generate a population of B cells with new antigen specificities. Some of these cells may be specific for self antigens. It is now known that two receptor ligand families play an important role in regulating T cell expansion in the periphery after contact with antigen and these same molecules are probably involved in deleting autoreactive lymphocyte in the periphery. Peripheral deletion of CD4+ T cells seems to be dependent on signaling through Fas. Deficiency in this pathway fails to delete T cells and develop severe autoimmune disease. Sometimes T cells are not deleted but become unresponsive to antigen stimulation specifically.
This is called clonal anergy. If antigen is eliminated, these anergic cells recover their responsiveness with time. One of the molecular mechanisms responsible for inducing anergy is signaling through CTLA4, expressed by activated T cells. Deficiency in this gene expression leads to severe autoimmune disease, such as human autoimmune thyroid disease.Mechanisms of peripheral tolerance include direct inactivation of effector T cells by either clonal deletion, conversion to regulatory T cells (Tregs) or induction of anergy.
Tregs, which are produced during development of T cells in the thymus, further suppress the effector functions of lymphocyte in the periphery. An antigen dependent on either central or peripheral tolerance is determined by its abundance in the organism. Peripheral tolerance of B cells is much less studied and is mainly mediated by B cell dependence on T cell help.Dendritic cells are a major population of cell responsible for initiating an adaptive immune response.
However, immature dendritic cells have ability to induce both CD4 and CD8 tolerance. These immature dendritic cells acquire antigen by endocytosis of apoptotic cells from the peripheral tissues and then present it to naïve T cells in the secondary lymphoid organs. If the T cell recognizes an antigen, it is either deleted or converted to Treg. Furthermore, BTLA+ dendritic cells were identified as a specialized population of antigen presenting cells (APCs) and are responsible for Treg conversion, upon maturation i.e. dendritic cells largely lose their tolerogenic capabilities.
Apart from dendritic cells, additional cell populations were identified that are able to induce antigen-specific T cell tolerance. These are mainly the members of lymph node stromal cells. Among them only fibroblastic reticular cells and lymph node stromal cells play a role in peripheral tolerance. Both of these have the ability to induce CD8 T cell tolerance by presentation of the endogenous antigen on MHC I molecules and CD 4 T cell tolerance by presentation of the peptide-MHC II complexes which are acquired from dendritic cells.Suppression of self reactive effector T cells by Tregs is another mechanism which protects the body from autoimmune reactions. Tregs suppress autoimmunity by several different mechanisms. These include degradation of IL-2 from the environment and secretion of tolerogenic cytokines IL-10 and TGF-?.
