Deficiency of thrombospondin-1 reduces Th17 differentiation and attenuates experimental autoimmune encephalomyelitis.
Transforming growth factor beta (TGF-beta) plays a role both in the induction of Treg and in the differentiation of the IL-17-secreting T cells (Th17) which drive inflammation in experimental autoimmune encephalomyelitis (EAE). We investigated the role that thrombospondin-1 (TSP-1) dependent activation of TGF-beta played in the generation of an encephalitic Th17 response in EAE. Upon immunization with myelin oligodendrocyte glycoprotein peptide (MOG(35-55)), TSP-1 deficient (TSP-1(null)) mice and MOG(35-55) TCR transgenic mice that lack of TSP-1 (2D2 x TSP-1(null)) exhibited an attenuated form of EAE, and secreted lower levels of IL-17. Adoptive transfer of in vitro-activated 2D2 x TSP-1(null) T cells induced a milder form of EAE, independent of TSP-1 expression in the recipient mice. Furthermore, in vitro studies demonstrated that anti-CD3/anti-CD28 pre-activated CD4+ T cells transiently upregulated latent TGF-beta in a TSP-1 dependent way, and such activation of latent TGF-beta was required for the differentiation of Th17 cells. These results demonstrate that TSP-1 participates in the differentiation of Th17 cells through its ability to activate latent TGF-beta, and enhances the inflammatory response in EAE.
Yang
Kaiyong
K
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Vega
Jose L
JL
Hadzipasic
Muhamed
M
Schatzmann Peron
Jean Pierre
JP
Zhu
Bing
B
Carrier
Yijun
Y
Masli
Sharmila
S
Rizzo
Luiz Vicente
LV
Weiner
Howard L
HL
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology*; D019700:Thrombospondin 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology
D020381:Interleukin-17; D011948:Receptors, Antigen, T-Cell; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma