CD57+ CD4 T Cells Underlie Belatacept-Resistant Allograft Rejection

Abstract

Belatacept is a B7-specific fusion protein used to prevent allograft rejection by blocking T cell costimulation. Generally efficacious, it fails to prevent acute rejection in a sizable minority of patients. In experimental models, memory T cells mediate costimulation blockade-resistant rejection (CoBRR), but this remains undefined in humans. To explore relationships between individuals’ immune cell phenotypes and CoBRR, we studied patients receiving belatacept or conventional calcineurin inhibitor-based immunosuppression. We identified a population of CD57+PD1− CD4 T cells present prior to transplantation that correlated with CoBRR. Contrary to data recognizing CD57 as a marker of senescence on CD8 T cells, we discovered a non-senescent, cytolytic phenotype associated with CD57 on CD4 T cells. Moreover, CD57+ CD4 T cells: expressed high levels of adhesion molecules implicated in experimental CoBRR; were CD28 negative; expressed a transcriptional phenotype broadly defining allograft rejection; and were shown to be present in rejecting human kidney allografts. These data implicate CD57+ CD4 T cells in clinical CoBRR and if prospectively validated, this characteristic could identify patients at higher risk for acute rejection on belatacept-based therapy.

Belatacept Combined With Transient Calcineurin Inhibitor Therapy Prevents Rejection and Promotes Improved Long-Term Renal Allograft Function

“…Current research efforts by our group and others seek to define potential immunologic parameters that might identify those patients at risk of rejection when treated with belatacept. (21, 22) Accurate identification of those patients who are at low risk of rejection may permit us to stratify those to avoid adjunct tacrolimus treatment as well as determine the optimal timing of the transition off of tacrolimus therapy for others.…”

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

“…In contrast, de Graav et al (14) reported the downregulation of surface CD28 on both CD4 + and CD8 + T cells as a potential escape mechanism from belatacept-mediated immune suppression. More recently, Espinosa et al (3) reported in a small study of 14 transplant recipients that the pretransplant frequency of a highly functional CD4 …”

“…The relatively high incidence of early aggressive T cell-mediated acute rejection is a significant impediment to the widespread use of belatacept in clinical transplantation, despite recent reports of improved long-term outcomes (1)(2)(3). High frequencies of alloreactive memory T cells have emerged as the major hypothesis to explain this emergence of belatacept-resistant cellular rejection.…”

Unusual CD4+CD28−T Cells and Their Pathogenic Role in Chronic Inflammatory Disorders

“…It should be noted that the loss of CD28 on CD4 T cells has been implicated in promoting immunosuppression resistance and allograft rejection (6970) due to the cytotoxic capacity of these cells. Very recently it was reported that increases in circulating CD4 + CD28 − CD57 + T cells prior to transplantation is associated with belatacept resistant rejection (BRR) post-transplantation (7172). Furthermore, cytomegalovirus-related, cytotoxic CD4 + CD28 − T cells potentiate kidney allograft dysfunction by glomerular endothelial injury in an NKG2D-dependent manner.…”