Are Resistant to Costimulation Blockade High CTLA-4 Compared with Th1 Cells and -Elicited Murine Th17 Cells Express Candida

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 co-stimulation 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-g + 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. T cells differentiate into distinct phenotypes based on the surrounding environment present during their initial interaction with cognate Ag and largely maintain this phenotype during challenge with recall or cross-reactive Ag (1–4). There is considerable evidence that pathogen-primed memory cells can cross-react with allogeneic Ag and mediate graft rejection, a process termed allogeneic heterologous immunity (5–9). Recent work has demonstrated that alloreactive T cells are inherently polyspecific (10–13), further elevating the potential importance of cross-reactive T cell responses in mediating alloreactivity. Heterologous T cell responses have been directly demonstrated to be a barrier to tolerance induction strategies such as costimulation blockade, highlighting the importance of understanding phenotypic diversity among pathogen-elicited T cell subsets (14, 15). The heterogeneity of T cell memory responses and their requirements for recall responses are critically important to the success of immunomodulatory therapy to prevent T cell–mediated rejection following transplantation of solid organs or bone marrow (6, 16, 17). The CD28/CTLA-4 costimulation blocker CTLA-4 Ig is efficacious for the treatment of rheumatoid arthritis (abatacept), and the derivative belatacept was recently approved for renal transplantation. However, belatacept …