Several different cell surface molecules control negative selection of medullary thymocytes

Repeated attempts to show that costimulation for negative selection is cont rolled by a single cell surface molecule have been unsuccessful. Thus, nega tive selection may involve multiple cell surface molecules acting in consor t. In support of this idea, we show here that at least three cell surface m olecules, namely CD28, CD5, and CD43, contribute to Fas-independent negativ e selection of the tolerance-susceptible population of heat-stable antigen (HSA)(hi)CD4(+)8(-) cells found in the medulla. The costimulatory function of these three molecules can be blocked by certain cytokines, IL-4 and IL-7 , and coinjecting these cytokines with antigen in vivo abolishes negative s election; Fas-dependent negative selection, however, is maintained. The res ults suggest that efficient negative selection requires the combined functi ons of at least four cell surface molecules: CD28, CD5, CD43, and Fas.