Peripheral tolerance

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in lymph nodes and tissues other than the thymus and bone marrow (after T and B cells egress from primary lymphoid organs). Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance can also serve a purpose in preventing an immune response to harmless food antigens and allergens. Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi were awarded the Nobel Prize in Physiology or Medicine in 2025 "for their discoveries concerning peripheral immune tolerance."

Self-reactive cells are subject to clonal deletion or clonal diversion. Both processes of peripheral tolerance control the presence and production of self-reactive immune cells. Deletion of self-reactive T cells in the thymus is only 60–70% efficient, and naive T cell repertoire contains a significant portion of low-avidity self-reactive T cells. These cells can trigger an autoimmune response, and there are several mechanisms of peripheral tolerance to prevent their activation. Antigen-specific mechanisms of peripheral tolerance include persistence of T cell in quiescence, ignorance of antigen and direct inactivation of effector T cells by either clonal deletion, conversion to regulatory T cells (Tregs) or induction of anergy. Tregs, which are also generated during thymic T cell development, further suppress the effector functions of conventional lymphocytes in the periphery. Dendritic cells (DCs) participate in the negative selection of autoreactive T cells in the thymus, but they also mediate peripheral immune tolerance through several mechanisms.

Dependence of a particular antigen on either central or peripheral tolerance is determined by its abundance in the organism. B cells have a lower probability that they will express cell surface markers to pose the threat of causing an autoimmune attack. What little is known about peripheral tolerance of B cells indicate that it is largely mediated by B cell dependence on T cell help. However, as B cells adjust their specificities in the germinal center, the self-reacting ones do tend to be selected against through unknown means.