Tolerance is specific immunologic unresponsiveness (i.e., an immune response to a certain antigen [or epitope] does not occur, although the immune system is otherwise functioning normally). In general, antigens that are present during embryonic life are considered “self” and do not stimulate an immunologic response (i.e., we are tolerant to those antigens). The lack of an immune response in the fetus is caused by the deletion of self-reactive T-cell precursors in the thymus (Figure 66–1). On the other hand, antigens that are not present during the process of maturation (i.e., that are encountered first when the body is immunologically mature) are considered “nonself” and usually elicit an immunologic response. Although both B cells and T cells participate in tolerance, it is T-cell tolerance that plays the primary role.
Production of T-cell tolerance in the thymus.
The main process by which T lymphocytes acquire the ability to distinguish self from nonself occurs in the fetal thymus (see Chapter 58). This process, called clonal deletion, involves the killing of T cells (“negative selection”) that react against antigens (primarily self major histocompatibility complex [MHC] proteins) present in the fetus at that time. (Note that exogenous substances injected into the fetus early in development are treated as self.) The self-reactive cells die by a process of programmed cell death called apoptosis. Tolerance to self acquired within the thymus is called central tolerance, whereas tolerance acquired outside the thymus is called peripheral tolerance.
For negative selection and clonal deletion to be efficient, the thymic epithelial cells must display a vast repertoire of “self” proteins. A transcriptional regulator called the autoimmune regulator (AIRE) enhances the synthesis of this array of self proteins. Mutations in the gene encoding the AIRE protein result in the development of an autoimmune disease called autoimmune polyendocrinopathy. The AIRE transcription factor also functions in the peripheral lymphoid organs such as the spleen and lymph nodes, where it contributes to peripheral tolerance.
Peripheral tolerance is necessary because some antigens are not expressed in the thymus and therefore some self-reactive T cells are not killed in the thymus. There are several mechanisms involved in peripheral tolerance: Some self-reactive T cells are killed, some are not activated, and others are suppressed by regulatory T cells producing inhibitory cytokines. Clonal anergy is the term used to describe self-reactive T cells that are not activated because proper costimulation does not occur (Figure 66–2). Clonal ignorance refers to self-reactive T cells that ignore self antigens. These self-reactive T cells are either kept ignorant by physical separation from the target antigens (e.g., the blood–brain barrier) or ignore self antigens because the antigens are present in such small amounts.
Clonal anergy outside the thymus. A: B7 protein on the ...