The Activation and Inactivation of Mature CD 4 T cells: A Case for Peripheral Self–Nonself Discrimination

The establishment of central tolerance to most self‐antigens results in a repertoire of mature peripheral lymphocytes specific for foreign and peripheral self‐antigens. The framework that single, mature lymphocytes are inactivated by antigen, whereas their activation requires lymphocyte cooperation, accounts for diverse observations and incorporates a mechanism of peripheral tolerance. This framework accounts for the generalizations that the sustained activation by antigen of most B cells and CD 8 T cells requires CD 4 T helper cells; in the absence of CD 4 T cells, antigen can inactivate these B cells and CD 8 T cells. In this sense, CD 4 T cells are the guardians of the fate of most B cells and CD 8 T cells when they encounter antigen. I argue here that the single‐lymphocyte/multiple‐lymphocyte framework for the inactivation/activation of lymphocytes also applies to CD 4 T cells. I consider within this framework a model for the activation/inactivation of CD 4 T cells that is consistent with the large majority of contemporary observations, including significant clinical observations. I outline the grounds why I feel this model is more plausible than the contemporary and predominant pathogen‐associated molecular pattern ( PAMP ) and Danger Models for CD 4 T cell activation. These models are based upon what I consider the radical premise that self–nonself discrimination does not exist at the level of mature CD 4 T cells. I explain why I feel this feature renders the PAMP and Danger Models somewhat implausible. The model I propose, in contrast, is conservative in that it embodies such a process of self–nonself discrimination.