Purpose: We have shown that CD57+PD1- CD4 T cells play a role in belatacept-resistant rejection, but their mechanism of action is incompletely defined. Potential mechanisms include loss of CD28 expression, adhesion molecule acquisition, and consolidation of an activated phenotype. In these studies, we explored the in vitro biology of these cells to gain insights into their development and further studied the stability of these cells in patients following transplantation.

Methods: Peripheral blood mononuclear cells (PBMCs) from healthy controls were non-stimulated, or stimulated with αCD3 beads alone, αCD3 and αCD28 beads, or allogeneic antigen. PBMCs from 50 kidney transplant recipients treated with non-belatacept based therapies were obtained at baseline, 1 month, 3 months, 6 months and 1 year post transplant to analyze the longitudinal stability of CD57+PD1- CD4 T cells.

Results: We found that in vitro stimulation increases expression of CD57, and that CD57+ CD4 T cells are proliferative and express high levels of granzyme B. CD57+ CD4 T cells express high levels of adhesion molecules previously implicated in costimulation blockade resistant rejection, and that CD57 serves as a unifying indication of CD2, LFA1, and VLA4 upregulation. Furthermore, while antigen experience induces CD28 loss, it does not confer activation; rather CD57 expression flags activated cells resistant to belatacept. Interestingly, we find that CD57+PD1- CD4 T cells are virtually non-existent in the healthy population, but are significantly increased in 35% of patients with renal failure (p<0.05), possibly due to chronic inflammation. CD57high populations persist at least 1 year following transplantation.

Conclusion: CD57+PD1- CD4 T cells are highly activated, proliferative, are present in 35% of kidney transplant recipients at baseline and persist following transplantation. These cells maintain their increased expression of adhesion molecules and remain poised to mediate rejection. The ability to identify these cells and characterize a means to target them would offer the possibility for therapy conversion to belatacept.

CITATION INFORMATION: Espinosa J, Stempora L, Townsend R, Kirk A. CD57+ CD4 T Cells Persist in the Periphery Following Kidney Transplantation. Am J Transplant. 2016;16 (suppl 3).

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