Journal
FASEB JOURNAL
Volume 29, Issue 3, Pages 1019-1028Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.14-264507
Keywords
granzyme; interferon; Listeria; cytokine; cytotoxicity
Categories
Funding
- U.S. National Institutes of Health (NIH) [R03-AI090231, RC4-AI092624, R34-AI100789, R21-AT004160, R03-CA164399]
- NIH National Institute of Dental and Craniofacial Research [T32DE014320]
- National Council of Science and Technology, Mexico (CONACYT)
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Innate CD8(+) T cells are a heterogeneous population with developmental pathways distinct from conventional CD8(+) T cells. However, their biology, classification, and functions remain incompletely understood. We recently demonstrated the existence of a novel population of chemokine (C-X-C motif) receptor 3 (CXCR3)-positive innate CD8(+) T cells. Here, we investigated the functional properties of this subset and identified effector molecules and pathways which mediate their function. Adoptive transfer of IL-15 activated CXCR3(+) innate CD8(+) T cells conferred increased protection against Listeria monocytogenes infection in susceptible IFN-gamma(-/-) mice compared with similarly activated CXCR3(-) subset. This was associated with enhanced proliferation and IFN-gamma production in CXCR3(+) cells. Further, CXCR3(+) innate cells showed enhanced cytotoxicity against a tumor cell line in vitro. In depth analysis of the CXCR3(+) subset showed increased gene expression of Ccl5, Klrc1, CtsW, GP49a, IL-2R beta, Atp5e, and Ly6c but reduced IFN-gamma R2 and Art2 beta. Ingenuity pathway analysis revealed an up-regulation of genes associated with T-cell activation, proliferation, cytotoxicity, and translational initiation in CXCR3(+) populations. Our results demonstrate that CXCR3 expression in innate CD8(+) T cells defines a subset with enhanced cytotoxic potential and protective antibacterial immune functions. Immunotherapeutic approaches against infectious disease and cancer could utilize CXCR3(+) innate CD8(+) T-cell populations as novel clinical intervention strategies.
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