Abstract
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)gammat, RORalpha, IL-21 and IL-23R. The expression of the type 17 master regulator RORgammat 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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
CD8-Positive T-Lymphocytes / cytology
-
CD8-Positive T-Lymphocytes / immunology
-
CD8-Positive T-Lymphocytes / metabolism*
-
Cell Differentiation / drug effects
-
Cell Differentiation / genetics
-
Cell Differentiation / immunology
-
Cell Line, Tumor
-
Cytotoxicity, Immunologic / immunology
-
Encephalomyelitis, Autoimmune, Experimental / genetics
-
Encephalomyelitis, Autoimmune, Experimental / immunology
-
Encephalomyelitis, Autoimmune, Experimental / metabolism
-
Flow Cytometry
-
Gene Expression / drug effects
-
Granzymes / metabolism
-
Green Fluorescent Proteins / genetics
-
Green Fluorescent Proteins / metabolism
-
Immunoblotting
-
Interferon-gamma / metabolism
-
Interleukin-17 / metabolism*
-
Interleukin-6 / pharmacology
-
Interleukins / pharmacology
-
Mice
-
Mice, Inbred C57BL
-
Nuclear Receptor Subfamily 1, Group F, Member 3
-
Receptors, Retinoic Acid / genetics
-
Receptors, Retinoic Acid / metabolism
-
Receptors, Thyroid Hormone / genetics
-
Receptors, Thyroid Hormone / metabolism
-
Reverse Transcriptase Polymerase Chain Reaction
-
STAT3 Transcription Factor / genetics
-
STAT3 Transcription Factor / metabolism
-
T-Lymphocytes, Cytotoxic / cytology
-
T-Lymphocytes, Cytotoxic / immunology
-
T-Lymphocytes, Cytotoxic / metabolism*
-
T-Lymphocytes, Helper-Inducer / cytology
-
T-Lymphocytes, Helper-Inducer / immunology
-
T-Lymphocytes, Helper-Inducer / metabolism*
-
Transforming Growth Factor beta / pharmacology
Substances
-
Interleukin-17
-
Interleukin-6
-
Interleukins
-
Nuclear Receptor Subfamily 1, Group F, Member 3
-
Receptors, Retinoic Acid
-
Receptors, Thyroid Hormone
-
Rorc protein, mouse
-
STAT3 Transcription Factor
-
Stat3 protein, mouse
-
Transforming Growth Factor beta
-
Green Fluorescent Proteins
-
Interferon-gamma
-
Granzymes
-
interleukin-21