Central Tolerance

Central tolerance refers to the negative selection step in T cell differentiation. It occurs in the thymus, where newly recombined T cell receptors are screened against a bevy of self-antigens and overactive clones are deleted. See Positive and Negative Selection of T Cells.

Clonal Deletion – T cells that recombine a TCR with a high affinity for MHC or for self antigens are deleted in the thymus as part of the selection and central tolerance process. Evidence suggests that high affinity self-MHC interactions mark a T cell clone for deletion.

Clonal Diversion – Regulatory T Cells – Some autoreactive T cells can be re-directed into a regulatory function. Induction of the FoxP3 gene leads to a host of anti-inflammatory functions, resulting in a Regulatory T cell (TREG). TREGS are a specialized class of T cells that groom and control T cell populations. They do so by secreting anti-inflammatory cytokines, via direct cell-to-cell contact and reprogramming and by directly regulating antigen presenting cell interaction with T cells. Evidence suggests that low affinity self-MHC interactions divert Autoreactive T cells into a regulatory function.

 

Peripheral Tolerance

Although central tolerance mechanisms are tightly regulated and highly effective, the sheer number of TCR combinations means sometimes an autoreactive T cell is exported from the thymus. While AIRE expression of non-thymic antigens is broad, it does not express every possible protein in the body. Combined with potential mutation, injury, and transformation of tissues, a secondary mechanism exists to turn off or delete T cells which attack host tissue. This process is known as peripheral tolerance.

Peripheral tolerance is especially likely to occur for T cells whose cognate antigen is: a) derived from food (as in celiac disease), b) is only expressed in developmental processes or in abnormal expression of developmental genes or c) is only displayed during a chronic infection. The two mechanisms for peripheral tolerance are T cell anergy and clonal deletion. Anergy and clonal deletion are not mutually exclusive fates- sometimes anergic T cells, upon chronic re-exposure to their antigen, eventually undergo deletion.  

T cell Anergy – An anergic T cell is not apoptotic or dying, but is instead in a prolonged state of unresponsiveness. Typical activation of a T cell requires ligation of the TCR (to MHC-antigen) and the addition of costimulatory molecules (CD28, B7, etc). Anergy occurs in the absence of this second signal- or costimulation or with a different costimulatory molecule.

These alternative molecules include programmed death receptor 1 (PD-1). PD1 ligation activates pathways that interfere with TCR-signaling, causing a loss of the pro-inflammatory cytokines the T cell would normally produce. Additionally, PD-1 ligation inhibits clonal expansion of antigen specific cells, limiting damage from self-reactive T cells.  CTLA-4 is another ligand which can cause anergy. Ligation of CTLA4 to the B7 costimulatory family of molecules delays cell-cycle progression, inhibiting or ending clonal expansion of that T cell lineage.

Anergy is frequently induced by tolerogenic dendritic cells, which ligate the TCR but fail to express or deliver costimulatory molecules.

Some microorganisms secrete virulence factors which can trigger clonal deletion or anergy.

Clonal deletion – In the periphery, clonal deletion is triggered by chronic stimulation with a self-reactive cognate antigen. The antigen is sometimes self-derived, but can also be the result of a chronic infection. T cells which are chronically stimulated will eventually be deleted via Fas-ligation or Bim activation by stromal cells of the lymph nodes. Fas and Bim are distinct pathways that share an end result- the ordered death program known as apoptosis and the deletion of that T cell.

Dr. Kerry Maxine Leehan is a AAAS Science and Technology Policy Fellow at the Millennium Challenge Corporation in Washington DC. Dr. Leehan is a human immunologist with a special interest in T cells and autoimmune disease and holds a PhD in Pathology and an MS in Microbiology & Immunology.

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