CTLA-4 (CD152) enhances the Tc17 differentiation program.
Although CD8(+) T cells that produce IL-17 (Tc17 cells) have been linked to host defense, Tc17 cells show reduced cytotoxic activity, which is the characteristic function of CD8(+) T cells. Here, we show that CTLA-4 enhances the frequency of IL-17 in CD8(+) T cells, indicating that CTLA-4 (CD152) specifically promotes Tc17 differentiation. Simultaneous stimulation of CTLA-4(+/+) and CTLA-4(-/-) T cells in cocultures and agonistic CTLA-4 stimulation unambiguously revealed a cell-intrinsic mechanism for IL-17 control by CTLA-4. The quality of CTLA-4-induced Tc17 cells was tested in vivo, utilizing infection with the facultative intracellular bacterium Listeria monocytogenes (LM). Unlike CTLA-4(+/+) Tc17 cells, CTLA-4(-/-) were nearly as efficient as Tc1 CTLA-4(+/+) cells in LM clearance. Additionally, adoptively transferred CTLA-4(-/-) Tc17 cells expressed granzyme B after rechallenge, and produced Tc1 cytokines such as IFN-γ and TNF-α, which strongly correlate with bacterial clearance. CTLA-4(+/+) Tc17 cells demonstrated a high-quality Tc17 differentiation program ex vivo, which was also evident in isolated IL-17-secreting Tc17 cells, with CTLA-4-mediated enhanced upregulation of Tc17-related molecules such as IL-17A, RORγt, and IRF-4. Our results show that CTLA-4 promotes Tc17 differentiation that results in robust Tc17 responses. Its inactivation might therefore represent a central therapeutic target to enhance clearance of infection.
Department of Pediatrics, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
Jonas
J
Pick
Aditya
A
Arra
Holger
H
Lingel
J Kolja
JK
Hegel
Magdalena
M
Huber
Gopala
G
Nishanth
Gerhard
G
Jorch
Klaus-Dieter
KD
Fischer
Dirk
D
Schlüter
Kerry
K
Tedford
Monika C
MC
Brunner-Weinzierl
D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D060908:CTLA-4 Antigen / Q000502:physiology*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D053804:Granzymes / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL
D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D020381:Interleukin-17; D053804:Granzymes
CTL; Costimulation; IFN-γ; IL-17; Ipilimumab; T-cell differentiation