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

Abstract

Effector and memory T cells may cross-react with allogeneic antigens to mediate graft rejection. While 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 antigen-specific model in which Th1 and Th17 cells were elicited via Mycobacterium tuberculosis (M.Tb) and Candida albicans (Candida) immunization, respectively. Candida immunization elicited a higher frequency of Th17 cells and conferred resistance to costimulation blockade following transplantation. Compared to the M.Tb group, Candida 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 to 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.

Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates

“…This is in accordance with a recent study reporting that CTLA4-Ig efficiency decreased in increasingly matured human T cells when stimulated with a CMV peptide or alloantigens (30). Collectively, our results suggest that human memory T cell reactivation in vitro is still CD28-dependent but tightly controlled by CTLA-4 and/or PD-L1 coinhibitory signals as described in mouse models of candida or Listeria monocytogenes infection (31,32).…”

Immunoregulation in Fungal Diseases

“…Perhaps most intriguing, however, was the additional observation that administration of anti-CTLA-4 antibodies during induction of a cell-mediated immune response to C. neoformans by vaccination improved the efficacy of vaccination and increased protection against subsequent infection with the organism. These data support and extend findings from a study demonstrating increased CTLA-4 expression on Th17 cells relative to Th1 cells in response to C. albicans infection [131]. Together, these studies may guide future vaccination strategies designed to elicit more potent recall responses from specific T cell subsets when traditional vaccination is combined with anti-CTLA-4 antibody treatment.…”

CTLA4-Ig in combination with FTY720 promotes allograft survival in sensitized recipients

“…However, the majority of those studies focused on tolerance induction that used a short treatment course of costimulation blockade, whereas in this study we treated continuously with CTLA4-Ig, which is similar to its clinical use (1,2,34). Furthermore, most of those studies were based on the adoptive transfer of donor-reactive memory T cells that drove the costimulation blockade-resistant rejection process (11,28,35,36). While that approach, especially when using graft-reactive TCR-transgenic T cell transfer, allows for elegant in-depth mechanistic analysis, their presence at nonphysiologically high TCR affinities and frequencies can lead to observations not replicated with endogenous T cells (37,38), and can also profoundly enhance endogenous graft-specific responses (39).…”