Immunological Tolerance: Mechanisms & Types

Historical Background

Types of Tolerance

1. Central Tolerance

T Cell Central Tolerance (Thymus)

• Developing thymocytes undergo positive selection in the cortex: those whose TCRs have no affinity for self-MHC die by neglect
• Cells that survive positive selection then undergo negative selection in the medulla: thymocytes whose TCRs bind self-antigen/MHC complexes with high affinity are killed by apoptosis (clonal deletion)
• Medullary thymic epithelial cells (mTECs) express the AIRE (autoimmune regulator) gene, which drives ectopic expression of peripheral tissue-restricted antigens (e.g., insulin, thyroid antigens) in the thymus - enabling deletion of T cells reactive to these distant-tissue antigens before they ever leave the thymus
• Loss-of-function mutations in AIRE cause autoimmune polyglandular syndrome type 1 (APS-1), proving how critical this mechanism is
• Some self-reactive T cells that survive negative selection differentiate into natural regulatory T cells (nTregs/tTregs) rather than being deleted, adding a layer of active suppression

B Cell Central Tolerance (Bone Marrow)

• When immature B cells strongly recognize self-antigens in the bone marrow, they can undergo receptor editing: the immunoglobulin gene rearrangement machinery is reactivated and the B cell tries to express a new, non-self-reactive receptor
• It is estimated that one-quarter to one-half of all mature B cells have undergone receptor editing
• If receptor editing fails, the self-reactive B cell is deleted by apoptosis
• B cell tolerance is therefore maintained primarily by receptor editing > clonal deletion > anergy (in that order of importance)

2. Peripheral Tolerance

a) Clonal Anergy

• Requires two signals for T-cell activation: Signal 1 (antigen-MHC + TCR) and Signal 2 (costimulation, e.g., CD28 binding B7/CD80/CD86 on APCs)
• If a T cell encounters antigen presented by a non-professional APC lacking costimulatory molecules, Signal 1 occurs without Signal 2 - the T cell becomes functionally unresponsive (anergic) rather than activated
• Anergic cells are alive but incapable of responding to subsequent stimulation
• CTLA-4 (expressed on activated T cells and constitutively on Tregs) competes with CD28 for B7 binding but delivers an inhibitory signal instead of activation. CTLA-4-deficient mice develop fatal lymphoproliferative autoimmunity
• PD-1 (programmed death-1) binds PD-L1/PD-L2 on many cell types and similarly blocks T cell activation - a key mechanism exploited by tumors to evade immune responses (now targeted by checkpoint inhibitors)
• Anergy also affects B cells: if they encounter self-antigen in peripheral tissue without T cell help, they become unresponsive and are excluded from lymphoid follicles

b) Deletion by Apoptosis (Activation-Induced Cell Death, AICD)

• Repeatedly stimulated or self-antigen-recognizing T cells undergo programmed death
• Mitochondrial (intrinsic) pathway: regulated by the BCL-2 family. BIM (a BH3-only sensor protein) is activated by strong self-antigen signals, activates BAX/BAK, leading to mitochondrial permeability and caspase activation. Survival factors (growth factor signals) keep BCL-2/BCL-XL high to counteract this
• Death receptor (extrinsic) pathway: activated T cells upregulate both Fas (CD95) and Fas Ligand (FasL/CD95L). Fas-FasL interaction triggers caspase-8 and apoptosis - this is the main mechanism of AICD
• Mutations in Fas or FasL cause autoimmune lymphoproliferative syndrome (ALPS) in humans, confirming the importance of deletion in peripheral tolerance

c) Suppression by Regulatory T Cells (Tregs)

• CD4+ T cells that express CD25 (IL-2Rα chain) and the transcription factor FOXP3 are called regulatory T cells
• Tregs develop mainly in the thymus (natural/thymic Tregs) upon recognition of self-antigens but can also be induced in the periphery (induced Tregs/iTregs)
• They suppress immune responses through:
  • Expressing CTLA-4 constitutively, stripping B7 from APCs and preventing costimulation
  • Secreting immunosuppressive cytokines: IL-10, TGF-β, and IL-35
  • Competing for IL-2 (via high CD25 expression), depriving effector T cells of survival signals
• FOXP3 mutations cause IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) - a severe systemic autoimmune disease in infants, proving the indispensability of Tregs
• Tregs also prevent rejection of the fetus (paternal alloantigens), inflammatory reactions to commensal gut bacteria, and regulate tissue repair in skin, muscle, and lung
• Clinical interest: Treg transfer trials for transplant rejection, GVHD, and autoimmune diseases; low-dose IL-2 to preferentially expand Tregs in patients

d) Immunological Ignorance

• Some peripheral self-antigens exist at concentrations too low or in locations too sequestered (immunologically privileged sites: eye, testis, CNS) to effectively activate T cells
• Naive autoreactive T cells may coexist with their target antigen without mounting a response - a passive form of tolerance
• This can break down during infection or inflammation, which upregulates costimulators and releases sequestered antigens

Summary Table

Key Clinical Correlations