We demonstrate that Ly-6A.2 expression on T cells inhibits their growth, both in the thymus and periphery. The growth inhibitory effects observed in the thymus occur when Ly-6A.2 is expressed ectopically on developing cells that normally do not express this protein. Diminished amount of LAT in the CD4 - CD8 - double negative (DN) subset, enhanced apoptosis of the CD4 + CD8 + double positive (DP) cells and altered selected TCR-V repertoire is observed in Ly-6A.2 dysregulated thymocytes. These results also suggest the importance of regulated expression of Ly-6A.2 on developing T cells and also provides clues related to the mechanism underlying the thymic block. Ly-6A.2 exerts antigen-specific growth inhibitory effects on CD4 + peripheral T cells when precociously over-expressed on the cell surface. CD4 T expressing dysregulated Ly-6A.2 cells exhibited reduced Ca 2+ flux upon stimulation, indicating membrane proximal events were altered. A major significance of these observations is that Ly-6A.2 might regulate clonal expansion of CD4 + T cells induced by a foreign antigen. Surprisingly, Ly-6A.2 over-expression on CD4 + T cells generates a Th2 promoting factor, IL-4, and may therefore play a role in Th2 differentiation.|The chance observation that ectopic expression of Ly-6A.2 in MHC I and II-deficient mice rescued the CD4 + T cell population was intriguing and provided a golden opportunity to examine the nature of the T cell repertoire that exists prior to positive and negative selection. We were surprised to note that the pre-selected T cell repertoire exhibited considerable reactivity to MHC. These observations might explain the phenonmenon of allogenic reactivity by mature CD4 + T cells.