T-cell tolerance: central and peripheral

Abstract

Somatic recombination of TCR genes in immature thymocytes results in some cells with useful TCR specificities, but also many with useless or potentially self-reactive specificities. Thus thymic selection mechanisms operate to shape the T-cell repertoire. Thymocytes that have a TCR with low affinity for self-peptide-MHC complexes are positively selected to further differentiate and function in adaptive immunity, whereas useless ones die by neglect. Clonal deletion and clonal diversion (Treg differentiation) are the major processes in the thymus that eliminate or control self-reactive T cells. Although these processes are thought to be efficient, they fail to control self-reactivity in all circumstances. Thus, peripheral tolerance processes exist wherein self-reactive T cells become functionally unresponsive (anergy) or are deleted after encountering self-antigens outside of the thymus. Recent advances in mechanistic studies of central and peripheral T-cell tolerance are promoting the development of therapeutic strategies to treat autoimmune disease and cancer and improve transplantation outcome.

Figure 1.

A model for the relationship between developmental outcome and TCR affinity for self-peptide–MHC. Cells with TCR that have a low affinity for self die by neglect. Those with an intermediate affinity are positively selected. High-affinity self-reactive clones can die via clonal deletion, and the threshold between positive and negative selection is hypothesized to be steep. Regulatory T cells (Treg) (yellow) have more highly self-reactive TCRs than most conventional T cells (purple). Some Tregs may have very highly self-reactive TCRs and are rescued from deletion via cytokine signaling or by virtue of having a second TCR (dotted line).

Figure 2.

Cell types in central tolerance. (Top) T cells are positively selected in the thymic cortex. Negative selection via clonal deletion can also occur in the cortex, but occurs frequently in the medulla. The thymic medulla is also the site for Treg differentiation. (Bottom) Cortical thymic epithelial cells (cTECs) express several unique genes that relate to proteolysis (cathepsin L, Ctsl; thymus-specific serine protease, TSSP; and β-5t proteasome subunit, β5t), which are essential for positive selection. Tissue-specific antigens (TSAs) can be directly presented by medullary thymic epithelial cells (mTECs) or cross-presented by DC (dotted line with arrow). RANKL, CD40L, and lymphotoxin (LT) expressed by SP thymocytes interact with their receptors on mTEC to promote the development of mTEC.

Figure 3.

Differential TCR signaling in clonal deletion and clonal diversion. TCR engagement of low-affinity self-peptide MHC ligands presented by cTECs transduces a signal that promotes survival and differentiation. TCR engagement with high-affinity self-peptide–MHC results in expression of Nur77 and Bim and apoptotic cell death. However, cytokines (TGF-β and IL-2) can prevent Treg progenitors from undergoing apoptosis and promotes the differentiation of Tregs.

Figure 4.

Peripheral tolerance. T-cell anergy is induced by inhibiting mTOR pathways or can be induced by tolerogenic DCs. The expression of Egr2, Cblb, Ctla4, DgkZ, and Pdcd1 genes is important in T-cell anergy. Lymph node stromal cells (LNSCs) express tissue-specific antigens (TSAs) and can mediate the deletion of self-reactive naive T cells.