Key Points

A decrease in effector memory donor-reactive CD4 T cells after transplantation was shown.

A decrease in polyfunctional (producing ≥2 cytokines) donor-reactive CD4 T cells was also seen.

Increased apoptosis in donor-reactive CD4 T cells after transplantation is also demonstrated.

Abstract

Following kidney transplantation, donor-specific hyporesponsiveness (DSH) may develop, defined as a lowered response of alloreactive T cells, specifically directed to donor Ag. This study aimed to characterize the nature of DSH through multiparameter flow cytometric assays measuring changes in phenotype and function of donor-reactive T cells after transplantation. This study characterized donor-reactive T cells, identified by CD137 expression, from the peripheral blood of stable human kidney transplant recipients (n = 47) before, at 3–5 y after, and >5 y after transplantation. The phenotype (T cell subset, differentiation status, and transcription factor expression) and function (proinflammatory cytokine production) of CD4+ and CD8+ donor-reactive CD137+ T cells was evaluated by both supervised and unsupervised analyses. Results demonstrated a decline in CD4+ donor-reactive T cells within the first 3–5 y after transplantation. Predominantly, the population of effector memory T cells capable of producing two or more proinflammatory cytokines was affected. This decline was strongly correlated with reduced proliferation of CD4+ T cells to donor Ag. The donor-reactive CD8+ T cells declined substantially only after >10 y. The frequency of T cells reactive to unrelated alloantigens did not alter significantly after transplantation, excluding an aspecific effect of immunosuppressive medication. After transplantation, an increase in donor Ag-induced apoptosis was found, specifically within the donor-reactive CD4+ memory T cell subsets. In conclusion, a significant decrease in donor-reactive polyfunctional effector memory CD4+ T cells underlies the development of DSH in kidney transplant recipients, which is likely mediated by specific activation-induced cell death.

Footnotes

This work was supported by the Dutch Kidney Foundation GANDALF study (project number 18PhD08).

The online version of this article contains supplemental material.

Abbreviations used in this article:

7-AAD7-aminoactinomycin DCMcentral memoryDSHdonor-specific hyporesponsivenessEMeffector memoryEMRACD45RA+ effector memoryFlowSOMFlow Self-Organizing MapP/IPMA and ionomycinReceived May 13, 2022.Accepted August 1, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.