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 shaper 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 are insufficient to in all circumstances. Thus, peripheral tolerance processes exists, wherein self-reactive T cells become functional 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.

Distinct mechanisms mediate naïve and memory CD8 T-cell tolerance

“…Central tolerance that results in deletion of high-avidity autoreactive Tcells occurs in the thymus during T-cell development (1,2). The deletion process is rendered more robust by the action of the Aire system, which promotes expression of nonthymic, tissuespecific proteins in thymic medullary epithelial cells (3).…”

Promiscuity Promotes Tolerance

“…The quasi-random rearrangement of gene segments encoding the Ag-specific receptors of lymphocytes occasionally generates specificities capable of recognizing the body's own constituents. Because these autoreactive specificities are potentially dangerous to the organism's health, multiple mechanisms have evolved to eliminate or inhibit the cells displaying them (1). Certain of the tolerance-inducing mechanisms operate within the primary lymphoid organs, the thymus for T cells and the fetal liver or bone marrow for B cells (termed central tolerance), whereas others exert their impact in the periphery, either within peripheral lymphoid organs or in tissues undergoing an immune response (peripheral tolerance).…”

To affinity and beyond: Harnessing the T Cell receptor for cancer immunotherapy

“…Central tolerance encompasses the mechanisms in the thymus that are in place to insure lack of T cell reaction to self-peptide upon entry into the periphery. 20 Clonal deletion, elimination of TCRs that present with high affinity to self peptide, and clonal diversion, conversion of moderate to high affinity TCRs to regulatory T cell (Tregs) lineage are the key processes that impact central tolerance. 21,22 Events that lead to central tolerance are key to the development of TCRs for adoptive cell therapy.…”

“…35 The precise mechanism of how high affinity and low affinity TCRs are discriminated between in the thymus remains unknown and further discovery of this process is important to the field of TCR engineering for immunotherapy. 20 …”