ImmunologyTier 2Medical Sciences concept

Central and peripheral T-cell tolerance mechanisms (negative selection, anergy, Treg)

Core concept

Central tolerance - thymus

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Double-positive thymocyte meets self-peptide-MHC on cortical epithelium

no binding -> death by neglect (the majority)
low/intermediate affinity -> positive selection -> survives, becomes CD4 or CD8
high affinity (medullary epithelium and dendritic cells)
- -> negative selection = clonal deletion by apoptosis
- -> or diversion into thymic (natural) Treg

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AIRE (autoimmune regulator) in medullary thymic epithelial cells promiscuously transcribes tissue-restricted antigens (insulin, thyroglobulin, retinal proteins) so they can be shown to developing T cells
- AIRE mutation -> APECED / APS-1 (AR): chronic mucocutaneous candidiasis + hypoparathyroidism + Addison's, and anti-IFN and anti-IL-17/IL-22 autoantibodies
Central tolerance is inevitably incomplete - not every self-antigen is expressed in the thymus, and affinity thresholds are imperfect. Peripheral mechanisms are the backup

Peripheral tolerance

Anergy - signal 1 (TCR-MHC) without signal 2 (CD28-B7) -> functional unresponsiveness
Deletion - repeated stimulation -> Fas/FasL activation-induced cell death (Fas/FASLG mutation -> ALPS: lymphadenopathy, splenomegaly, cytopenias, raised double-negative TCR-alpha/beta CD4-CD8- T cells**)
Suppression by Tregs
Ignorance - immune-privileged sites (eye, testis, CNS) behind barriers; sympathetic ophthalmia is what happens when this fails

Regulatory T cells (CD4+ CD25-high FOXP3+)

Mechanism	Detail
CTLA-4	Binds B7 with far higher affinity than CD28 and physically strips B7 off the APC (trans-endocytosis)
IL-2 sequestration	High-affinity CD25 (IL-2Ralpha) deprives conventional T cells of IL-2 - Tregs need IL-2 but cannot make it
Inhibitory cytokines	IL-10, TGF-beta, IL-35
Direct killing	Granzyme/perforin against effector cells and APCs
Metabolic	CD39/CD73 -> adenosine

FOXP3 mutation -> IPEX (X-linked): Immune dysregulation, Polyendocrinopathy (neonatal T1DM, thyroiditis), Enteropathy (intractable diarrhoea), X-linked; eczema, cytopenias - fatal without HSCT
CTLA4 haploinsufficiency and LRBA deficiency -> CVID-like disease with autoimmunity, lymphocytic infiltration, enteropathy - treated with abatacept (CTLA-4-Ig)
Two checkpoint molecules, two diseases: AIRE breaks central tolerance, FOXP3 breaks peripheral tolerance

Immune checkpoint inhibitors deliberately break peripheral tolerance
- Anti-CTLA-4 (ipilimumab) acts early, in the lymph node, on priming -> more frequent and more severe irAEs, especially colitis and hypophysitis
- Anti-PD-1/PD-L1 acts late, in tissue -> pneumonitis, thyroiditis, hepatitis, myocarditis
- Combination therapy -> highest irAE rate; treat with corticosteroids, then infliximab (not for hepatitis - use MMF)
CTLA-4 biology in reverse: abatacept (CTLA-4-Ig) blocks costimulation in RA and in CTLA4/LRBA deficiency
Low-dose IL-2 expands Tregs preferentially - under trial in SLE and GVHD
Tolerance failure is the final common pathway of autoimmunity: the same self-antigen becomes pathogenic only when tolerance to it is lost, which is why molecular mimicry and epitope spreading matter
Thymectomy or thymoma disrupts central tolerance -> myasthenia gravis, pure red cell aplasia, Good's syndrome

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