Purpose: T cells with a memory phenotype mediate costimulation blockade (CoB) resistant rejection (RR), and early CoBRR has been seen in patients on belatacept-based immunosuppression. Hypothesizing that T cell phenotype might identify patients at risk for CoBRR, we studied banked samples from patients receiving belatacept-based CoB, specifically quantifying terminally differentiated memory cells expressing CD57, a marker of T cell senescence, and related this expression to clinical outcome.

Methods: Renal allograft recipients receiving belatacept according to labeled indication were enrolled in an IRB-approved tissue acquisition protocol. Peripheral blood obtained prior to drug administration was analyzed by 9-color flow cytometry, interrogating for markers of memory, differentiation, activation, exhaustion and senescence. PCR analysis of telomere length, a parameter relevant to senescence, was also performed. Within 7 months of transplantation, 9 patients experienced acute cellular rejection (ACR) and 5 were rejection-free.

Results: Patients who experienced ACR had a markedly higher percentage of CD4+57+PD1- T cells (p<0.01) at transplantation compared to those without rejection. Typically considered a marker of senescence, CD57 expression on CD4 T cells paradoxically correlated with expression of proliferation marker Ki67 (p<0.01), and was not associated with shorter telomere length. These relationships were limited to the CD4 compartment. CD8+57+PD1- T cells marginally trended higher in ACR patients (p<0.24), but CD57 expression on CD8 T cells was associated with more traditional indices of senescence (reduced Ki67 expression, shorter telomere length).

Discussion: We have identified a CD4 T cell phenotype that strongly correlates with belatacept-resistant rejection. CD57 has been commonly described as a marker of cell senescence, a state of persistent cell cycle arrest. However, the non-senescent (Ki67+, normal telomere length) phenotype associated with CD57, and its limitation to CD4 T cells suggests that in this setting it is a flag for activated T follicular helper (TFH) cells. TFH cells are antigen-experienced cells critical for certain immune responses and driven by alternative costimulatory pathways including CD154 and the CD28 homologue ICOS. These data are consistent with known pre-clinical synergies between B7-CoB and CD154 or ICOS blockade, and support prospective studies to validate means of identifying patients most suited for belatacept-based therapy.

Townsend, R.: Employee, Bristol-Myers Squibb. Kirk, A.: Grant/Research Support, Bristol-Myers Squibb.

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