QUANTITATIVE IMPACT OF THYMIC CLONAL DELETION ON THE T-CELL REPERTOIRE

Interactions between major histocompatibility complex (MHC) molecules expressed on stromal cells and antigen-specific receptors on T cells s hape the repertoire of mature T lymphocytes emerging from the thymus. Some thymocytes with appropriate receptors are stimulated to undergo d ifferentiation to the fully mature state (positive selection), whereas others with strongly autoreactive receptors are triggered to undergo programmed cell death before completing this differentiation process ( negative selection). The quantitative impact of negative selection on the potentially available repertoire is currently unknown. To address this issue, we have constructed radiation bone marrow chimeras in whic h MHC molecules are present on radioresistant thymic epithelial cells (to allow positive selection) but absent from radiosensitive hematopoi etic elements responsible for negative selection. In such chimeras, th e number of mature thymocytes was increased by twofold as compared wit h appropriate control chimeras. This increase in steady-state numbers of mature thymocytes was not related to proliferation, increased reten tion, or recirculation and was accompanied by a similar two- to threef old increase in the de novo rate of generation of mature cells. Taken together, our data indicate that half to two-thirds of the thymocytes able to undergo positive selection die before full maturation due to n egative selection.