title: Innate signals overcome acquired TCR signaling pathway regulation and govern the fate of human CD161(hi) CD8α⁺ semi-invariant T cells.
abstract: Type 17 programmed CD161(hi)CD8α(+) T cells contribute to mucosal immunity to bacteria and yeast. In early life, microbial colonization induces proliferation of CD161(hi) cells that is dependent on their expression of a semi-invariant Vα7.2(+) TCR. Although prevalent in adults, CD161(hi)CD8α(+) cells exhibit weak proliferative and cytokine responses to TCR ligation. The mechanisms responsible for the dichotomous response of neonatal and adult CD161(hi) cells, and the signals that enable their effector function, have not been established. We describe acquired regulation of TCR signaling in adult memory CD161(hi)CD8α(+) T cells that is absent in cord CD161(hi) cells and adult CD161(lo) cells. Regulated TCR signaling in CD161(hi) cells was due to profound alterations in TCR signaling pathway gene expression and could be overcome by costimulation through CD28 or innate cytokine receptors, which dictated the fate of their progeny. Costimulation with IL-1β during TCR ligation markedly increased proinflammatory IL-17 production, while IL-12-induced Tc1-like function and restored the response to TCR ligation without costimulation. CD161(hi) cells from umbilical cord blood and granulocyte colony stimulating factor-mobilized leukaphereses differed in frequency and function, suggesting future evaluation of the contribution of CD161(hi) cells in hematopoietic stem cell grafts to transplant outcomes is warranted.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. cturtle@fhcrc.org
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Turtle
authors.forename: Jeff
authors.initials: J
authors.lastname: Delrow
authors.forename: Rochelle C
authors.initials: RC
authors.lastname: Joslyn
authors.forename: Hillary M
authors.initials: HM
authors.lastname: Swanson
authors.forename: Ryan
authors.initials: R
authors.lastname: Basom
authors.forename: Laura
authors.initials: L
authors.lastname: Tabellini
authors.forename: Colleen
authors.initials: C
authors.lastname: Delaney
authors.forename: Shelly
authors.initials: S
authors.lastname: Heimfeld
authors.forename: John A
authors.initials: JA
authors.lastname: Hansen
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Riddell
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D016827:CD8 Antigens / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005312:Fetal Blood; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D016207:Cytokines; C527203:KLRB1 protein, human; D055651:NK Cell Lectin-Like Receptor Subfamily B; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta