Candida-elicited murine Th17 cells express high Ctla-4 compared with Th1 cells and are resistant to costimulation blockade.
Effector and memory T cells may cross-react with allogeneic Ags to mediate graft rejection. Whereas the costimulation properties of Th1 cells are well studied, relatively little is known about the costimulation requirements of microbe-elicited Th17 cells. The costimulation blocker CTLA-4 Ig has been ineffective in the treatment of several Th17-driven autoimmune diseases and is associated with severe acute rejection following renal transplantation, leading us to investigate whether Th17 cells play a role in CD28/CTLA-4 blockade-resistant alloreactivity. We established an Ag-specific model in which Th1 and Th17 cells were elicited via Mycobacterium tuberculosis and Candida albicans immunization, respectively. C. albicans immunization elicited a higher frequency of Th17 cells and conferred resistance to costimulation blockade following transplantation. Compared with the M. tuberculosis group, C. albicans-elicited Th17 cells contained a higher frequency of IL-17(+)IFN-γ(+) producers and a lower frequency of IL-10(+) and IL-10(+)IL-17(+) cells. Importantly, Th17 cells differentially regulated the CD28/CTLA-4 pathway, expressing similarly high CD28 but significantly greater amounts of CTLA-4 compared with Th1 cells. Ex vivo blockade experiments demonstrated that Th17 cells are more sensitive to CTLA-4 coinhibition and therefore less susceptible to CTLA-4 Ig. These novel insights into the differential regulation of CTLA-4 coinhibition on CD4(+) T cells have implications for the immunomodulation of pathologic T cell responses during transplantation and autoimmunity.
Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA 30322.
Scott M
SM
Krummey
Tamara L
TL
Floyd
Danya
D
Liu
Maylene E
ME
Wagener
Mingqing
M
Song
Mandy L
ML
Ford
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D000946:Antigens, Fungal / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology*; D002176:Candida albicans / Q000276:immunology*; D007114:Immunization; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
D000942:Antigens, Bacterial; D000946:Antigens, Fungal; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007371:Interferon-gamma