title: SLAT regulates CD8+ T cell clonal expansion in a Cdc42- and NFAT1-dependent manner.
abstract: After antigenic stimulation, CD8(+) T cells undergo clonal expansion and differentiation into CTLs that can mount a strong defense against intracellular pathogens and tumors. SWAP-70-like adapter of T cells (SLAT), also known as Def6, is a novel guanine nucleotide exchange factor for the Cdc42 GTPase and plays a role in CD4(+) T cell activation and Th cell differentiation by controlling Ca(2+)/NFAT signaling, but its requirement in CD8(+) T cell response has not been explored. Using a range of transgenic and knockout in vivo systems, we show that SLAT is required for efficient expansion of CD8(+) T cells during the primary response but is not necessary for CTL differentiation. The reduced clonal expansion observed in the absence of SLAT resulted from a CD8(+) T cell-intrinsic proliferation defect and a reduced IL-2-dependent cell survival. On a molecular level, we show that Def6 deficiency resulted in defective TCR/CD28-induced NFAT translocation to the nucleus in CD8(+) T cells. Constitutively active Cdc42 or NFAT1 mutants fully restored the impaired expansion of Def6(-/-) CD8(+) T cells. Taken together, these data describe a new and pivotal role of SLAT-mediated NFAT activation in CD8(+) T cells, providing new insight into the signaling pathways involved in CD8(+) T cell proliferation.
authors.affiliation: Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Feau
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Schoenberger
authors.forename: Amnon
authors.initials: A
authors.lastname: Altman
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bécart
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002999:Clone Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D020764:cdc42 GTP-Binding Protein; C494007:Nfatc2 protein, mouse; C473249:Def6 protein, mouse