title: Duality of the murine CD8 compartment.
abstract: CD8αβ plays crucial roles in the thymic selection, differentiation, and activation of some, but not all, CD8(+) T cells, whereas CD8αα 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 D(b)/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 Ca(2+) and to kill via perforin/granzyme. Their strong Fas/FasL-mediated cytotoxicity and IFN-γ response were signaled via a Ca(2+)-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 Ca(2+), p56(lck), and nuclear factor of activated T cells-dependent pathway. Deep sequencing of millions of TCRα chain transcripts revealed that the TCR repertoires of preimmune CD8(+) T cells were highly diverse, but those of LCMV D(b)/GP33-specific CTL, especially from KO mice, were narrow. The immune repertoires exhibited biased use of Vα 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 Ca(2+) signaling but permissive for Ca(2+)-independent, PI3K-dependent signaling. This duality of the CD8 compartment may provide organisms with broader protective immunity.
authors.affiliation: Ludwig Centre for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Genolet
authors.forename: Julie
authors.initials: J
authors.lastname: Leignadier
authors.forename: Magne
authors.initials: M
authors.lastname: Østerås
authors.forename: Laurent
authors.initials: L
authors.lastname: Farinelli
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Stevenson
authors.forename: Immanuel F
authors.initials: IF
authors.lastname: Luescher
mesh_terms: D000818:Animals; D001483:Base Sequence; D016827:CD8 Antigens / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D059014:High-Throughput Nucleotide Sequencing; D007111:Immunity, Cellular / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism* / Q000502:physiology
chemical_list: D016827:CD8 Antigens; C433839:CD8alphabeta antigen; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D019869:Phosphatidylinositol 3-Kinases; D002118:Calcium