Increased Pretransplant Frequency of CD28+ CD4+ TEM Predicts Belatacept-Resistant Rejection in Human Renal Transplant Recipients

Abstract

While most human T cells express the CD28 costimulatory molecule constitutively, it is well-known that age, inflammation, and viral infection can drive the generation of CD28null T cells. In vitro studies have demonstrated that CD28null cell effector function is not impacted by the presence of the CD28 costimulation blocker belatacept. As such, a prevailing hypothesis suggests that CD28null cells may precipitate costimulation blockade-resistant rejection. However, CD28+ cells possess more proliferative and multi-functional capacity, factors that may increase their ability to successfully mediate rejection. Here, we performed a retrospective immunophenotypic analysis of adult renal transplant recipients who experienced acute rejection on belatacept treatment as compared to those that did not. Intriguingly, our findings suggest that patients possessing higher frequency of CD28+ CD4+ TEM prior to transplant were more likely to experience acute rejection following treatment with a belatacept-based immunosuppressive regimen. Mechanistically, CD28+ CD4+ TEM contained significantly more IL-2 producers. In contrast, CD28null CD4+ TEM isolated from stable belatacept-treated patients exhibited higher expression of the 2B4 coinhibitory molecule as compared to those isolated from patients who rejected. These data raise the possibility that pre-transplant frequencies of CD28+ CD4+ TEM could be used as a biomarker to predict risk of rejection following treatment with belatacept.

Selective CD28 blockade attenuates CTLA-4–dependent CD8+ memory T cell effector function and prolongs graft survival

“…This notion is supported by recent evidence from both the NHP renal allograft model and human kidney transplant recipients showing that increased frequencies of CD28 + effector memory T cells (T EM ) were associated with increased risk of acute rejection (24,58). Thus, in contrast with earlier suggestions that CD28 null memory T cells were the mediators of belatacept-resistant rejection, these new data suggest that less differentiated memory T cells that retain expression of CD28 may underlie these rejection episodes (59), and therefore that CD28 may indeed still be an important therapeutic target in this cell population in order to limit acute rejection mediated by memory T cells and improve long-term outcomes following transplantation.…”

“…on to experience acute rejection on belatacept actually possessed increased frequencies of CD28 hi memory T cells relative to those who did not experience rejection (24), suggesting that it is in fact a CD28 + memory T cell population that underlies belatacept-resistant rejection. If these cells are reliant on CD28 signals for optimal activation, why do they fail to be controlled in the setting of belatacept therapy?…”

Memory T‐cell exhaustion and tolerance in transplantation

“…32 These animals all exhibited diagnostic criteria for acute renal antibody-mediated rejection (ie, high serum titers of donor-specific alloantibody, minimal T-cell infiltration, and intense C4d deposition in the grafts) and this rejection response was reversed by B-cell depletion. CD4 + memory T-cell populations have been best described for their ability to augment donor-specific antibody responses.…”

“…[32][33][34][35] Compared to naive laboratory mice, humans have increased frequencies and numbers of memory cells, which may influence our ability to translate successful tolerization strategies from animal models to humans. [32][33][34][35] Compared to naive laboratory mice, humans have increased frequencies and numbers of memory cells, which may influence our ability to translate successful tolerization strategies from animal models to humans.…”

“…An increased total memory cell pool increases the potential alloreactive memory pool. 32,33 Based on its mechanism of action, it is tempting to speculate that belatacept-resistant rejection must be mediated by memory T cells that lack CD28. 35 While there are certainly additional phenotypic differences between memory T cells that may portend greater or less risk, and multiple rejection mechanisms at play, it is clear in order to achieve tolerance the number of donor-reactive memory T cells must be minimized in allograft recipients.…”