IMPAIRED NEGATIVE SELECTION IN CD28-DEFICIENT MICE

T cell antigen receptors (TCR) expressed on developing T cells can rea ct with self-peptides presented by proteins encoded by the major histo compatibility complex (MHC). Depending on the relative strength of the se interactions, thymocytes are either negatively selected as potentia lly autoreactive and deleted or positively selected to become mature T cells. Developmental selection may also be regulated by signals in ad dition to those mediated through the TCR. In peripheral T cells, the C D28 receptor plays an important role in enhancing the survival and exp ansion of T cells activated by TCR engagement. Therefore, we have inve stigated the role of CD28 in regulating the selection of thymocytes us ing CD28-deficient mice. Surprisingly, we found a 50% increase in cell number in the thymi of CD28-deficient compared to wildtype mice, sugg esting that CD28 might play a role in negative selection. Negative sel ection of double-positive thymocytes was found to be significantly red uced in response to either antigen or antibody crosslinking of the TCR complex in CD28-deficient animals. This was not due to a generalized defect in thymocyte survival as thymocytes from CD28-deficient and wil dtype mice displayed similar sensitivity to apoptosis initiated by eit her gamma-irradiation or dexamethasone, In contrast to its role in T c ell activation and survival in the peripheral immune system, the CD28 receptor appears to participate in the intracellular signaling events that result in negative selection in the thymus, (C) 1998 Academic Pre ss.