Enhanced GITR/GITRL interactions augment IL-27 expression and induce IL-10-producing Tr-1 like cells.
The glucocorticoid-induced TNFR-related (GITR) protein is a coactivating receptor that is constitutively expressed on Treg cells and induced on activated T cells. To better under-stand the role of long-term GITR signaling, we generated a mouse that constitutively expresses GITR ligand (GITRL) on APCs that mimics the physiological distribution of GITRL in vivo. Despite a five-fold expansion of the Treg-cell pool, there is increased activation and depletion of naive T cells in the transgenic (Tg) mice, suggesting that the increased number of Treg cells cannot fully suppress T-cell activation. Interestingly, GITRL Tg mice have multiorgan lymphocytic infiltrates yet display no overt autoimmunity, indicating the existence of a compensatory immunoregulatory mechanism(s). In the spleens and tissue infiltrates ofGITRL Tg mice, we found increased numbers of Foxp3(-)  IL-10-producing type 1 regulatory T (Tr-1)-like cells that suppress naïve T-cell proliferation in an IL-10-dependent fashion. Increased IL-27 production from Tg APCs and activation of c-Maf in the Tr1-like cells suggest a possible mechanism for their induction. Our results demonstrate that enhanced GITR/GITRL interactions have a pleiotropic role on the regulation of T-cell responses, which includes promoting the differentiation of Tr-1-like cells, which contribute to the maintenance of peripheral T-cell tolerance.
Inflammation and Immunology, Pfizer, Cambridge, MA 02118, USA. yijun.carrier@pfizer.com
Yijun
Y
Carrier
Matthew J
MJ
Whitters
Joy S
JS
Miyashiro
Timothy P
TP
LaBranche
Hilda E
HE
Ramon
Stephen E
SE
Benoit
Mark S
MS
Ryan
Sean P
SP
Keegan
Heath
H
Guay
John
J
Douhan
Mary
M
Collins
Kyri
K
Dunussi-Joannopoulos
Quintus G
QG
Medley
D000818:Animals; D015551:Autoimmunity; D051858:Forkhead Transcription Factors / Q000032:analysis; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000502:physiology*; D016753:Interleukin-10 / Q000096:biosynthesis*; D007378:Interleukins / Q000096:biosynthesis*; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D048069:Tumor Necrosis Factors / Q000502:physiology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; C556062:IL10 protein, mouse; C486767:Il27 protein, mouse; D007378:Interleukins; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors; D016753:Interleukin-10