8-27 The final stage of T-cell maturation occurs in the thymic medulla.
After surviving positive and negative selection, thymocytes complete their maturation in the thymic medulla and then emigrate to peripheral lymphoid organs. Their final maturation results in changes to the T-cell receptor signaling machinery. Whereas an immature double-positive or single-positive thymocyte stimulated through the T-cell receptor will undergo apoptosis, a mature single-positive thymocyte responds by proliferating. The final maturation stage takes less than 4 days, and functionally competent T cells then emigrate from the thymus into the bloodstream (Fig. 8.32). Emigration requires recognition of the lipid molecule sphingosine 1-phosphate (S1P) by the G-proteincoupled receptor S1PR1, which is expressed by thymocytes during their final maturation. S1P is present in high concentration in blood and lymph, and mature thymocytes seem to be drawn toward it. Mature thymocytes also express CD62L (L-selectin), a lymph-node homing receptor that facilitates the localization of mature naive T cells to peripheral lymphoid organs after their emigration from the thymus.
8-28 T cells that encounter sufficient quantities of self antigens for the first time in the periphery are eliminated or inactivated.
Many autoreactive T cells are purged during their development in the thymus. As discussed in Section 8-23, this negative selection process is facilitated by the AIRE protein, which promotes the expression of many tissue-specific antigens in thymic medullary epithelial cells. Nonetheless, not all self antigens are expressed in the thymus, and some autoreactive T cells complete their maturation and migrate to the periphery. Our understanding of the fates of autoreactive T cells in the periphery comes mainly from the study of mice transgenic for self-reactive T-cell receptors. In some cases, T cells reacting to self antigens in the periphery are eliminated. This usually follows a brief period of activation and cell division, and so is known as activation-induced cell death. In other cases, the self-reactive cells may be rendered anergic. When studied in vitro, these anergic T cells prove refractory to signals delivered through the T-cell receptor.
The question immediately arises: if the encounter of a mature naive lymphocyte with a self antigen leads to cell death or anergy, why does this not also happen to a mature lymphocyte that recognizes a pathogen-derived antigen? The answer is that infection sets up inflammation, which induces the expression of co-stimulatory molecules on the antigen-presenting dendritic cells and the production of cytokines promoting lymphocyte activation. The outcome of an encounter with antigen in these conditions is the activation, proliferation, and differentiation of the lymphocyte to effector-cell status. In the absence of infection or inflammation, dendritic cells still process and present self antigens, but in the absence of co-stimulatory and other signals, any interaction of a mature lymphocyte with its specific antigen seems to result in a tolerance-inducing (tolerogenic) signal from the antigen receptor.
Summary.