Duality of the murine CD8 compartment

Abstract

CD8aβ plays crucial roles in the thymic selection, differentiation, and activation of some, but not all, CD8+ T cells, whereas CD8aa does not. To investigate these roles, we produced mice that expressed transgene P14 T-cell receptor β (TCRβ) chain and CD8β or did not (WT and KO mice, respectively). The primary CD8+ T-cell response to acute lymphocytic choriomeningitis virus (LCMV) infection was predominantly Db/GP33 specific and CD8 independent in KO mice and was mostly CD8 dependent in WT mice. Cytotoxic T lymphocytes (CTL) from KO mice failed to mobilize intracellular Ca2+ and to kill via perforin/ granzyme. Their strong Fas/FasL-mediated cytotoxicity and IFN-γ responsewere signaled via a Ca2+-independent, PI3K-dependent pathway. This was also true for 15-20% of CD8-independent CTL found in WT mice. Conversely, the perforin/granzyme-mediated killing and IFN-γ response of CD8-dependent CTL were signaled via a Ca2+, p56lck , and nuclear factor of activated T cells-dependent pathway. Deep sequencing of millions of TCRa chain transcripts revealed that the TCR repertoires of preimmune CD8+ T cells were highly diverse, but those of LCMV Db/GP33-specific CTL, especially from KO mice, were narrow. The immune repertoires exhibited biased use of Va segments that encoded different complementary-determining region 1α (CDR1α) and CDR2α sequences. We suggest that TCR from WT CD8-independent T cells may engage MHC-peptide complexes in a manner unfavorable for efficient CD8 engagement and Ca2+ signaling but permissive for Ca 2+-independent, PI3K-dependent signaling. This duality of the CD8 compartment may provide organisms with broader protective immunity.