CD57+ CD4 T Cells Underlie Belatacept-Resistant Allograft Rejection

• DOI: 10.1111/ajt.13613
• Publication Date: 2015-11-25T05:24:50Z
• Authors: J. Espinosa; F. Herr; G. Tharp; S. Bosinger; M. Song; A.B. Farris; R. George; J. Cheeseman; L. Stempora; R. Townsend; A. Durrbach; A.D. Kirk
• Keywords: Adult; CD4-Positive T-Lymphocytes; Graft Rejection; Graft Survival; Drug Resistance; Allografts; Flow Cytometry; Kidney Function Tests; Immunohistochemistry; Kidney Transplantation; Polymerase Chain Reaction; 3. Good health; Abatacept; 03 medical and health sciences; CD57 Antigens; 0302 clinical medicine; Humans; Kidney Failure, Chronic; Immunologic Memory; Immunosuppressive Agents; Follow-Up Studies; Glomerular Filtration Rate; Oligonucleotide Array Sequence Analysis

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 individual patients' 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 nonsenescent, 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(-) , 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. If prospectively validated, this characteristic could identify patients at higher risk for acute rejection on belatacept-based therapy.