B and T lymphocyte attenuator (BTLA) is a negative regulator of T cell activation, but its function in vivo is not well characterized. Here we show that mice deficient in full-length BTLA or its ligand, herpesvirus entry mediator, had increased number of memory CD8+ T cells. The memory CD8+ T cell phenotype resulted from a T cell-intrinsic perturbation of the CD8+ T cell pool. Naive BTLA-deficient CD8+ T cells were more efficient than wild-type cells at generating memory in a competitive antigen-specific system. This effect was independent of the initial expansion of the responding antigen-specific T cell population. In addition, BTLA negatively regulated antigen-independent homeostatic expansion of CD4+ and CD8+ T cells. These results emphasize two central functions of BTLA in limiting T cell activity in vivo.
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