Central tolerance

Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self.^[1] The concept of central tolerance was proposed in 1959 by Joshua Lederberg,^[2] as part of his general theory of immunity and tolerance, and is often mistakenly attributed to MacFarlane Burnet.^[3] Lederberg hypothesized that it is the age of the lymphocyte that defines whether an antigen that is encountered will induce tolerance, with immature lymphocytes being tolerance sensitive. Lederberg's theory that self-tolerance is 'learned' during lymphocyte development was a major conceptual contribution to immunology, and it was experimentally substantiated in the late 1980s when tools to analyze lymphocyte development became available. Central tolerance is distinct from peripheral tolerance in that it occurs while developing immune cells are still present in the primary lymphoid organs (the thymus and bone-marrow), prior to export into the periphery. Such peripheral tolerance is generated after the cells reach the periphery by regulatory T cells. Such regulatory T cells can be considered both central tolerance and peripheral tolerance mechanisms, as they can be generated from self(or foreign)-reactive T cells in the thymus (during T cell differentiation), but can also exert immune suppression in the periphery on other self(or foreign)-reactive T cells.

Requirement for central tolerance

At first, all T and B cell precursors have an identical genome, but then receptor variety is generated by a combination of 3 mechanisms. The first mechanism is the combination of the alpha- and beta-chain for the T cell receptor (TCR), or of the heavy and light chain for the B cell receptor (BCR), each encoded by 2 different gene copies - the unused copy gets inactivated. T cell and B cell receptor genes contain multiple gene segments (the V, D, and J segments) which need to be physically rearranged by somatic gene rearrangement - called V(D)J-recombination - to make a functional gene. At the site of segment recombination, additional bases will be inserted, which results in additional diversity - called junctional diversity - and gives rise to the complementarity determining regions (CDR). These random combinations and base insertions allow the creation of T cell receptors and antibodies against antigens which the host has never encountered during its evolutionary history, and is thus a powerful defense against rapidly evolving pathogens. Conversely, the random nature of junctional diversity creates, by chance, a population of T cells and B cells that are self-reactive (i.e., recognize an antigen which is a constituent component of the host).

In mammals, central tolerance is established in the thymus (T cells)^[4][5] and bone marrow (B cells). These are the two primary lymphoid organs where T cells and B cells mature. During the maturation phases of both T cells and B cells, the cells are sensitive to self-antigens. Unlike mature peripheral lymphocytes, which become activated upon encountering their specific antigen, the immature lymphocytes respond to antigen stimulation by undergoing a rewiring of cellular processes. The response to antigen at this stage depends on the properties of the antigen, the cell type, and the developmental stage, and can lead to the cell becoming non-responsive (anergic), undergoing directed suicide (negative selection), altering its antigen receptor (receptor editing), or entering a regulatory lineage.

As this tolerance is dependent on encountering self-antigens during maturation, lymphocytes can only develop central tolerance towards those antigens present in primary lymphoid organs. In the case of B cells, this is limited to ubiquitous and bone-marrow specific antigens and additional antigens imported by circulation (either as raw antigens or presented by circulating dendritic cells). The thymus has an additional source of antigen through the action of the transcription factors, Aire and Fezf2, which allow the expression of organ-specific antigens such as insulin in the thymus.

Mechanisms of central tolerance

B cell tolerance

The recognition of antigens by the immature B cells in the bone marrow is critical to the development of immunological tolerance to self. This process produces a population of B cells that do not recognize self-antigens but may recognize antigens derived from pathogens (non-self).

Immature B cells expressing only surface IgM molecules undergo negative selection by recognizing self-molecules present in the bone marrow. This antigen induced loss of cells from the B cell repertoire is known as clonal deletion. B cells may encounter two types of antigen, multivalent cell surface antigens or low valence soluble antigens:

• When immature B cells express surface IgM that recognizes ubiquitous self-cell-surface (i.e. multivalent) antigens (such as those of the MHC) they are eliminated by a process known as clonal deletion. These B cells are believed to undergo programmed cell death or apoptosis. However, there is an interval before apoptosis during which the self-reactive B cell may be rescued by further gene rearrangements (receptor editing) that may replace the self-reactive receptor with a new receptor, which is not auto-reactive.^[6]
• Immature B cells that bind soluble self-antigens (i.e. low valence) do not die but their ability to express IgM on their surfaces is lost (as a result of the downregulation in receptor synthesis due to the development of receptor tolerance - similar to the process seen in drug tolerance - through constant exposure to self-antigen). Thus, they migrate to the periphery only expressing IgD (pushed by the division of additional B cells) and are unable to respond to antigen. These B cells are said to be anergic. Only B cells that do not encounter antigen whilst they are maturing in the bone marrow can be activated after they enter the periphery. These cells bear both IgM and IgD receptors and constitute the repertoire of B cells that recognize foreign antigen.^[7]

Even if mature self-reacting B cells were to survive intact, they would very rarely be activated. This is because B cells need co-stimulatory signals from T cells as well as the presence of its recognized antigen to proliferate and produce antibodies (Peripheral tolerance). If mature peripheral B cells encounter multivalent antigen (e.g. cell surfaces) they are eliminated via apoptosis. If mature B cells recognize soluble antigen in the periphery in the absence of T cell help, they lose surface IgM receptors and become anergic.^[8]

T cell tolerance

T cells are selected for survival much more rigorously than B cells. They undergo both positive and negative selection to produce T cells that recognize self- major histocompatibility complex (MHC) molecules but do not recognize self-peptides. T cell tolerance is induced in the thymus.

Positive selection occurs in the thymic cortex. This process is primarily mediated by thymic epithelial cells, which are rich in surface MHC molecules. If a maturing T cell is able to bind to a surface MHC molecule in the thymus, it is saved from programmed cell death; those cells failing to recognize MHC on thymic epithelial cells will die. Thus, positive selection ensures that T cells only recognize antigen in association with MHC. This is important because one of the primary functions of T cells is to identify and respond to infected host cells as opposed to extracellular pathogens. The process of positive selection also determines whether a T cell ultimately becomes a CD4+ cell or a CD8+ cell: prior to positive selection, all thymocytes are double positive (CD4+CD8+) i.e. bear both co-receptors. During positive selection they are transformed into either CD4+CD8- or CD8+CD4- T cells depending on whether they recognize MHC II or MHC I, respectively.^[7]

T cells may also undergo negative selection in a process analogous to the induction of self-tolerance in B cells, this occurs in the cortex, at the cortico-medullary junction, and the medulla (mediated in the medulla predominately by medullary thymic epithelial cells (mTECs) and dendritic cells). mTEC display "self" antigens to developing T-cells and signal those "self-reactive" T-cells to die via programmed cell death (apoptosis) and thereby deleted from the T cell repertoire. This process is highly dependent on the ectopic expression of tissue specific antigens (TSAs) which is controlled by transcriptional regulators such as Aire and Fezf2.^[8]

This clonal deletion of T cells in the thymus cannot eliminate every potentially self-reactive T cell; T cells that recognize proteins only found at other sites in the body or only at certain times of development (e.g. after puberty) must be inactivated in the periphery. In addition, many self reactive T cells may not have sufficient affinity (binding strength) for the self antigen to be deleted in the thymus.

Regulatory T cells are another group of T cells maturing in the thymus, they are also involved with immune regulation.

Genetic diseases caused by defects in central tolerance

Genetic defects in central tolerance can lead to autoimmunity.

• Autoimmune Polyendocrinopathy Syndrome Type I is caused by mutations in the human gene AIRE. This leads to a lack of expression of peripheral antigens in the thymus, and hence a lack of negative selection towards key peripheral proteins such as insulin.^[9][10] Multiple autoimmune symptoms result.

See also

• Autoimmunity
• Immunology
• Peripheral tolerance

References