Central immune tolerance is the set of processes that establish immune tolerance during lymphocyte development in primary lymphoid organs. It operates principally in the thymus for T cells and the bone marrow for B cells. Developing cells that recognize the body’s own antigens may be eliminated, change their receptor specificity, or enter a regulatory lineage. These mechanisms reduce the potential for autoimmunity before lymphocytes join the mature immune population, but do not remove every self-reactive cell. (nature.com)
Biological basis
The immune system requires a diverse repertoire of antigen receptors to recognize many different foreign structures. In adaptive immunity, this diversity arises partly through V(D)J recombination, which assembles receptor genes during lymphocyte development. Receptor generation does not intrinsically distinguish foreign antigens from self-antigens: potentially harmful self-reactivity therefore occurs within the newly generated repertoire. Central tolerance imposes developmental checkpoints on these cells rather than preventing their initial formation. (pubmed.ncbi.nlm.nih.gov)
Central and peripheral immune tolerance are distinguished primarily by developmental stage and location. Central mechanisms act while lymphocytes develop in primary lymphoid organs; peripheral mechanisms restrain cells after they leave these sites. The distinction is not absolute for every cellular response. For example, reduced responsiveness can begin during B-cell development and remain important during subsequent peripheral maturation. Together, the checkpoints reduce self-reactivity while preserving a broad receptor repertoire. (pmc.ncbi.nlm.nih.gov)
T-cell selection in the thymus
Developing T cells, or thymocytes, are screened through interactions between their T-cell receptors and self-peptides displayed by major histocompatibility complex (MHC) molecules. Positive selection primarily occurs in the thymic cortex and allows cells capable of recognizing self-peptide–MHC complexes to continue developing. Cells that fail to receive adequate survival signals die by neglect. Positive selection establishes MHC recognition; it is not equivalent to the removal of dangerous self-reactivity. (ncbi.nlm.nih.gov)
Negative selection removes thymocytes whose interactions with self-antigens produce signals associated with excessive self-reactivity. This elimination, termed clonal deletion, occurs through apoptosis. It can occur at more than one developmental stage and in both cortical and medullary environments. The medulla is particularly important for screening against a diverse collection of tissue-associated antigens. Thymic epithelial cells and dendritic cells participate in this process as antigen-presenting cells. (pmc.ncbi.nlm.nih.gov)
Receptor affinity alone does not provide a universal numerical boundary between survival and deletion. Antigen abundance, the presenting cell, developmental timing, and the quality of receptor signaling influence the outcome. Consequently, descriptions of “weak” recognition causing survival and “strong” recognition causing deletion are useful approximations rather than complete accounts of thymocyte selection. (pubmed.ncbi.nlm.nih.gov)
Presentation of tissue-restricted self-antigens
Many self-antigens are normally associated with particular peripheral tissues. Medullary thymic epithelial cells nevertheless express a broad selection of these antigens, extending the range of self structures available for developmental screening. Antigens produced by epithelial cells can be presented directly or transferred to other thymic antigen-presenting cells, allowing additional routes of recognition by thymocytes. (pmc.ncbi.nlm.nih.gov)
The autoimmune regulator AIRE is important in this system. It promotes expression of numerous tissue-restricted antigen genes in medullary thymic epithelial cells. Experiments in AIRE-deficient mice demonstrated reduced thymic expression of peripheral antigens and organ-directed autoimmune responses, establishing a connection between thymic antigen expression and tolerance. AIRE is not responsible for all tissue-restricted antigen expression: research in mice identified FEZF2 as another regulator controlling a partly distinct antigen-expression program. (pubmed.ncbi.nlm.nih.gov)
Development of regulatory T cells
Not all self-reactive thymocytes are deleted. Some develop into regulatory T cells, which subsequently suppress immune responses and contribute to peripheral tolerance. This outcome redirects self recognition into a regulatory function rather than eliminating the cell. Experiments using defined self-peptides demonstrated that recognition of a self-antigen can promote thymic regulatory T-cell selection. (pubmed.ncbi.nlm.nih.gov)
The characteristic regulatory program includes expression of FOXP3. Development into this lineage depends on more than a simple intermediate position on a scale of receptor affinity. Experimental comparisons show that the specificity and quality of self-peptide recognition can distinguish regulatory differentiation from deletion. Thymic regulatory T-cell production thus connects a central developmental checkpoint with mechanisms that act throughout peripheral tissues. (pubmed.ncbi.nlm.nih.gov)
B-cell tolerance in bone marrow
Immature B cells are screened through the self-antigen recognition properties of their membrane-bound immunoglobulin receptors. A major corrective mechanism is receptor editing: additional immunoglobulin gene rearrangements, usually involving light-chain genes, can change receptor specificity. Unlike deletion, editing may preserve the developing cell while replacing a self-reactive receptor with one that permits further maturation. This mechanism was demonstrated experimentally in self-reactive bone-marrow B cells. (pubmed.ncbi.nlm.nih.gov)
Cells that remain strongly self-reactive may undergo developmental arrest and deletion. Other patterns of self-antigen exposure can induce anergy, a state of reduced functional responsiveness. The outcome depends on receptor signaling and antigen properties, including whether an antigen is soluble or displayed in a multivalent form. Editing, deletion, and reduced responsiveness therefore represent different responses to self recognition, rather than interchangeable names for one process. (pmc.ncbi.nlm.nih.gov)
Limits and relevance to disease
Central tolerance substantially reduces self-reactivity without making the mature repertoire entirely non-self-reactive. A study of human B-cell development found that self-reactive antibodies were common among early immature cells and were reduced at successive developmental checkpoints. The persistence of some self-reactive cells explains why peripheral control remains necessary. (pubmed.ncbi.nlm.nih.gov)
Failures of central tolerance can contribute to autoimmune disease. Human AIRE defects and experimental disruption of thymic antigen-expression programs provide evidence for this relationship. However, central tolerance is one component of a larger system: the presence of a self-reactive lymphocyte alone does not establish that it will cause tissue injury, because later checkpoints also influence whether that cell becomes functionally active. (pubmed.ncbi.nlm.nih.gov)