Enhanced GITR/GITRL interactions augment IL‐27 expression and induce IL‐10‐producing Tr‐1 like cells

• Published in: European journal of immunology Vol. 42; no. 6; pp. 1393 - 1404
• Main Authors: Carrier, Yijun, Whitters, Matthew J., Miyashiro, Joy S., LaBranche, Timothy P., Ramon, Hilda E., Benoit, Stephen E., Ryan, Mark S., Keegan, Sean P., Guay, Heath, Douhan, John, Collins, Mary, Dunussi‐Joannopoulos, Kyri, Medley, Quintus G.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.06.2012
• Subjects: Animals; Autoimmunity; Cell differentiation; Costimulation; Forkhead Transcription Factors - analysis; Glucocorticoid-Induced TNFR-Related Protein - physiology; Interleukin-10 - biosynthesis; Interleukins - biosynthesis; Lung - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Regulatory T cells; T-Lymphocytes, Regulatory - physiology; Tumor Necrosis Factors - physiology
• DOI: 10.1002/eji.201142162
• ISSN: 0014-2980

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.