Expression of Senescence Marker TIGIT Identifies Polyfunctional Donor-Reactive CD4+ T Cells Preferentially Lost After Kidney Transplantation

Abstract

Development of T-cell hyporesponsiveness to donor antigen may explain the substantial decreased risk for acute rejection in the years following kidney transplantation. The underlying mechanisms of donor-specific hyporesponsiveness (DSH) are largely unknown but may allow for lowering of immunosuppressive medication. Due to the onset of DSH being more rapid and pronounced in older recipients (+55 years), we hypothesized that immunosenescence/exhaustion of T lymphocytes would be a contributing factor. This study tested whether donor-reactive recipient T cells become hyporesponsive due to exhaustion from continuous stimulation by donor antigen. Circulating donor-reactive T cells of both young and elderly stable kidney transplant recipients (N=17) before and 3-5 years after transplantation were analyzed at the single cell level for expression of exhaustion markers by multi-parameter flow cytometry followed by unsupervised and unbiased clustering. Clusters containing cells of a particular expression profile with significant differential abundance after transplantation were identified and further analyzed. Unexpectedly, our results do not demonstrate an increase in exhausted donor antigen-reactive T cells post transplantation. Instead, we demonstrate a significant decrease in donor antigen-reactive CD4+ T cells expressing T cell immunoglobulin and ITIM domain (TIGIT) long after transplantation. Further analysis at earlier timepoints indicated that this decrease is already present at six months post transplantation. Characterization of these CD4+ T donor-reactive cells expressing TIGIT revealed them to have a predominantly central and effector memory T cell phenotype and a highly poly-functional cytokine expression profile. This study has therefore identified TIGIT as a marker for a previously undescribed polyfunctional donor-reactive CD4+ T cell population whose decline following kidney transplantation may explain development of DSH.

Immune Checkpoint Molecule TIGIT Regulates Kidney T Cell Functions and Contributes to AKI

“…43,44 Conversely, reduction in TIGIT-expressing polyfunctional CD41 T cells after kidney transplant enhanced tolerance and improved graft survival. 34 Our observation showing increased TIGIT expression after ischemic injury further implicates TIGIT in human AKI pathogenesis.…”

The Ratio of CD226 and TIGIT Expression in Tfh and PD-1+ICOS+Tfh Cells Are Potential Biomarkers for Chronic Antibody-Mediated Rejection in Kidney Transplantation

“…A phenomenon known as donor-specific hyporesponsiveness (DSH) has been described in some kidney transplant recipients and is associated with a good long-term prognosis. A study described the novel finding that TIGIT-expressing donor-reactive CD4 + T cells decreased several years after kidney transplantation, which could explain the development of DSH [ 37 ]. We investigated the populations of CD226 + Tfh and TIGIT + Tfh cells and calculated the ratio of CD226 + Tfh cells to TIGIT + Tfh cells.…”

The Value of Single-cell Technologies in Solid Organ Transplantation Studies

“…Single-cell studies can be valuable to identify biomarkers that could be predict rejection or tolerance following transplantation. 54,144,145 For example, Lau et al 54 identified via CyTOF a T-cell subset, distinct from classic T regulatory cells, that was associated with tolerance in pediatric liver transplant recipients. In addition, Pike et al 145 found that the pretransplant immune profile of the peripheral blood T cells was predictive for the risk of acute renal rejection in renal transplant recipients.…”