Regulatory T cell expressed MyD88 is critical for prolongation of allograft survival.
MyD88 signaling directly promotes T-cell survival and is required for optimal T-cell responses to pathogens. To examine the role of T-cell-intrinsic MyD88 signals in transplantation, we studied mice with targeted T-cell-specific MyD88 deletion. Contrary to expectations, we found that these mice were relatively resistant to prolongation of graft survival with anti-CD154 plus rapamycin in a class II-mismatched system. To specifically examine the role of MyD88 in Tregs, we created a Treg-specific MyD88-deficient mouse. Transplant studies in these animals replicated the findings observed with a global T-cell MyD88 knockout. Surprisingly, given the role of MyD88 in conventional T-cell survival, we found no defect in the survival of MyD88-deficient Tregs in vitro or in the transplant recipients and also observed intact cell homing and expression of Treg effector molecules. MyD88-deficient Tregs also fail to protect allogeneic bone marrow transplant recipients from chronic graft-versus-host disease, confirming the observations of defective regulation seen in a solid organ transplant system. Together, our data define MyD88 as having a divergent requirement for cell survival in non-Tregs and Tregs, and a yet-to-be defined survival-independent requirement for Treg function during the response to alloantigen.
Center for Transplantation Science, Department of Surgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.|Program in Immunology, Harvard University Division of Medical Sciences, Harvard University, Boston, MA, USA.
Christopher M
CM
Borges
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.
Dawn K
DK
Reichenbach
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Beom Seok
BS
Kim
Summer Immunology Research Program, Harvard University, Boston, MA, USA.|School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA.
Aditya
A
Misra
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.
Bruce R
BR
Blazar
Center for Transplantation Science, Department of Surgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
Laurence A
LA
Turka
D000818:Animals; D016026:Bone Marrow Transplantation; D023201:CD40 Ligand / Q000378:metabolism; D002470:Cell Survival; D005260:Female; D005434:Flow Cytometry; D017353:Gene Deletion; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D006086:Graft vs Host Disease; D016027:Heart Transplantation; D007249:Inflammation; D007519:Isoantigens; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000008:administration & dosage / Q000378:metabolism; D012867:Skin / Q000473:pathology; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D014184:Transplantation, Homologous
D007519:Isoantigens; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D023201:CD40 Ligand; D020123:Sirolimus
T cells; Treg; inflammation; transplantation