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Immune tolerance is maintained through central mechanisms (deletion of self-reactive lymphocytes in thymus and bone marrow) and peripheral mechanisms (anergy, suppression, deletion of self-reactive cells in secondary lymphoid organs). Defects in central tolerance (incomplete negative selection) or peripheral tolerance (Treg insufficiency, inadequate Fas/FasL) predispose to autoimmunity.
Examine how Aire and other genes control negative selection. Study how TGF-β and IL-2 maintain Treg function and how their loss triggers autoimmunity.
Central tolerance eliminates some, but not all, self-reactive cells; peripheral mechanisms must catch escaped self-reactive clones. Anergy is reversible under inflammatory conditions, so tolerance is not permanent without active suppression.
From thymic selection, you know that developing T cells are tested against self-peptide–MHC complexes: those that bind too strongly are eliminated by negative selection. From regulatory T cells, you know that a specialized population of CD4+ cells actively suppresses immune responses. Immune tolerance is the umbrella term for all the mechanisms that prevent the adaptive immune system from attacking the body's own tissues, and it operates at two complementary levels — central and peripheral — that together form a layered defense against autoimmunity.
Central tolerance occurs in the primary lymphoid organs where lymphocytes develop: the thymus for T cells and the bone marrow for B cells. In the thymic medulla, medullary epithelial cells use the transcription factor AIRE to express a sampling of tissue-specific proteins — molecules that would normally only be found in the pancreas, thyroid, or eye, for example. Developing T cells whose TCRs bind these self-peptide–MHC complexes with high affinity are eliminated by apoptosis (clonal deletion) or, in some cases, diverted into the regulatory T cell lineage. B cells undergo an analogous process in the bone marrow: immature B cells that strongly bind self-antigens are either deleted, rendered anergic, or undergo receptor editing — rearranging their light chain genes to generate a new, non-self-reactive BCR. Central tolerance is powerful but imperfect. Not every self-antigen is expressed in the thymus or bone marrow, and the threshold for deletion is set to preserve useful reactivity, meaning some self-reactive clones inevitably escape.
Peripheral tolerance catches what central tolerance misses. Three main mechanisms operate in the secondary lymphoid organs and tissues. First, anergy: when a T cell encounters its antigen presented without costimulatory signals (no B7 on the antigen-presenting cell), it becomes functionally unresponsive rather than activated — think of it as the T cell receiving signal 1 (TCR engagement) without signal 2 (costimulation), which produces paralysis instead of activation. Second, suppression: regulatory T cells (Tregs) actively inhibit self-reactive lymphocytes through contact-dependent mechanisms and secretion of immunosuppressive cytokines like IL-10 and TGF-β. Tregs are essential — their depletion causes rapid, multi-organ autoimmunity. Third, peripheral deletion: chronically stimulated self-reactive cells can be eliminated through the Fas-FasL pathway, where repeated antigen encounter triggers apoptosis rather than further proliferation.
The key insight is that tolerance is not a one-time event but an ongoing, active process. Anergy can be broken if inflammation provides the missing costimulatory signals — this is one route by which infections trigger autoimmune disease. Treg function must be continuously maintained through IL-2 signaling, and defects in Treg number or function lead to autoimmunity. The layered architecture — central deletion as the first filter, peripheral anergy and suppression as backup, and peripheral deletion as a last resort — reflects how dangerous a failure of tolerance can be, and why the immune system invests so heavily in redundant safeguards against self-reactivity.