TY - JOUR
T1 - Expression of Senescence Marker TIGIT Identifies Polyfunctional Donor-Reactive CD4+ T Cells Preferentially Lost After Kidney Transplantation
AU - van der List, Amy C.J.
AU - Litjens, Nicolle H.R.
AU - Klepper, Mariska
AU - Betjes, Michiel G.H.
N1 - Funding Information:
In an ongoing study (Gandalf study, project number: 18PhD08, funded by the Dutch Kidney Foundation) the effects of age on donor-reactive T cells are evaluated by studying a cohort of young (≤45 years) and elderly (>54 years) kidney transplant recipients.
Publisher Copyright:
© Copyright © 2021 van der List, Litjens, Klepper and Betjes.
PY - 2021/4/30
Y1 - 2021/4/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105941208&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.656846
DO - 10.3389/fimmu.2021.656846
M3 - Article
C2 - 33995373
AN - SCOPUS:85105941208
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 656846
ER -