Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 39, Issue 7, Pages 1716-1725Publisher
WILEY-BLACKWELL
DOI: 10.1002/eji.200939412
Keywords
CTL; EAE; ROR gamma t; STAT3; Tc17
Categories
Funding
- Deutsche Forschungsgerneinschaft [LO 396-1, GRK 767, SFB/TR22]
- Gemeinnijtzige Hertie-Stiftung [1.01.1/08/003]
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Activation of naive CD8(+) T cells with antigen in the absence of skewing cytokines triggers their differentiation into effector CTL, which induces death of target cells. We show that CD8(+) T cells activated in the presence of the cytokines IL-6 or IL-21 plus TGF-beta similar to CD4(+) T cells, develop into IL-17-producing (Tc17) cells. These cells display greatly suppressed cytotoxic function along with low levels of the CTL markers: T-box transcription factor Eomesodermin, granzyme B and IFN-gamma. Instead, these cells express hallmark molecules of Th17 program including retinoic acid receptor-related orphan receptor (ROR)gamma t, ROR alpha, IL-21 and IL-23R. The expression of the type 17 master regulator ROR gamma t is causally linked to Tc17 generation, because its overexpression stimulates production of IL-17 in the presence of IL-6 or IL-21. Both, upregulation of the type 17 program as well as suppression of CTL differentiation are STAT3 dependent. Furthermore, Tc17 cells producing IL-17 but not granzyme B are also detectable in EAE, a mouse model for multiple sclerosis. Our data point to the existence of mutually exclusive CTL and Tc17 developmental pathways in vitro and in vivo.
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