Selective CD28 Blockade Results in Superior Inhibition of Donor-Specific T Follicular Helper Cell and Antibody Responses Relative to CTLA4-Ig

Abstract

Donor-specific antibodies (DSAs) are a barrier to improved long-term outcomes after kidney transplantation. Costimulation blockade with CTLA4-Ig has shown promise as a potential therapeutic strategy to control DSAs. T follicular helper (Tfh) cells, a subset of CD4 T cells required for optimal antibody production, are reliant on the CD28 costimulatory pathway. We have previously shown that selective CD28 blockade leads to superior allograft survival through improved control of CD8 T cells relative to CTLA4-Ig, but the impact of CD28-specific blockade on CD4 Tfh cells is unknown. Thus, we identified and characterized donor-reactive Tfh cells in a murine skin transplant model and then used this model to evaluate the impact of selective CD28 blockade with an anti-CD28 domain antibody (dAb) on the donor-specific Tfh cell-mediated immune response. We observed that the anti-CD28 dAb led to superior inhibition of donor-reactive CXCR5 PD-1 Tfh cells, CD95 GL7 germinal center B cells and DSA formation compared with CTLA4-Ig. Interestingly, donor-reactive Tfh cells differentially upregulated CTLA4 expression, suggesting an important role for CTLA4 in mediating the superior inhibition observed with the anti-CD28 dAb. Therefore, selective CD28 blockade as a novel approach to control Tfh cell responses and prevent DSA after kidney transplantation warrants further study.

Impact of selective CD28 blockade on virus-specific immunity to a murine Epstein-Barr virus homolog

“…Second, our results show that the anti-CD28 dAb also better controls the GC B cell response over time following MHV infection (Figure 4), which is consistent with previously published results in the setting of transplantation 39. It is well established that the viral reservoir in MHV-68 infection is the GC B cell pool and that MHVinfected cells drive expansion of this population 23.…”

“…Second, our results show that the anti-CD28 dAb also better controls the GC B cell response over time following MHV infection ( Figure 4), which is consistent with previously published results in the setting of transplantation. 39 It is well established that the viral reservoir in MHV-68 infection is the GC B cell pool and that MHVinfected cells drive expansion of this population. 23 Thus, by reducing the reservoir available for infection and further propagation of the virus, anti-CD28 dAb treatment may result in a smaller pool of infected cells that necessitate CD8 + T cell-mediated immune surveillance, as we observed in Figure 4D.…”

Commentary: Belatacept Does Not Inhibit Follicular T Cell-Dependent B-Cell Differentiation in Kidney Transplantation

“…Kim et al demonstrate that CTLA4-Ig alters the germinal center and reduces the population of Tfh cells in the spleens of skin-sensitized mice, leading to reduction in alloantibody production ( 7 ). Badell et al also show inhibition of adoptively transferred donor-specific Tfh cells in the draining lymph nodes with CTLA4-Ig after skin transplantation in mice ( 8 ). Our study in non-human primates demonstrates that in a model of AMR using tacrolimus-based immunosuppression, subjects treated with belatacept showed reduced B-cell proliferation, number of CD4 + PD1 + T-cells, and production of IL-21 within the lymph nodes compared with those without belatacept treatment ( 9 ).…”

Memory T‐cell exhaustion and tolerance in transplantation

“…Using a mouse model of skin transplant, Badell et al show that selective CD28 blockade therapy is superior to CTLA-4Ig in suppressing donor-specific Tfh cells, germinal center B cells, as well as generation of DSA. 104 First, Badell et al show that compared to treatment with CTLA-4Ig, animals treated with selective CD28blockade had fewer overall numbers of Tfh cells in the draining lymph nodes after fully allogenic skin graft 104. The differential ef-fect of blocking CD80/86 vs blocking CD28 and maintaining CTLA-4 signaling in this study definitively associates T follicular helper cells as a viable target for costimulatory blockade to help induce allograft tolerance.…”