A Subset of Patients Accumulated Highly Differentiated CD4 & CD8 T Memory Cells Despite Having Long-Term Stable Graft Function.

Abstract

Introduction: Restriction of TCR Vb repertoire diversity has been associated with a poor-functioning graft whereas the maintenance of a diverse TCR Vb repertoire has been ascribed to a well-functioning kidney. We monitored the usage of the TCR Vb repertoire in patients with long-term stable graft function to see if restriction of the TCR Vb repertoire could be prospective of graft dysfunction in these patients. Methods: 131 Kidney recipients with long term stable graft function (median time post-transplantation 7.78 years) were monitored for more than 6 years. Upon enrollment, the TCR Vb repertoire was characterized using TcLandscape. Phenotyping of CD4 and CD8 T cells was performed using multicolor flow cytometry. Results: We found that, whereas the majority of the patients with stable graft function retained a diverse TCR repertoire, 45 out of 131 patients displayed a restricted TCR Vb repertoire despite their stable graft function. Interestingly, these patients also had a significantly decreased frequency of CD45RA+CD197+ naïve CD4 and CD8 T cells (p<0.001), that was inversely correlated with an increase in CD8+CD45RA+CD197- terminally differentiated effector memory (TEMRA) cell frequencies (p<0.001) CD4+CD45RA-CD197- effector memory (EM) and CD4+CD45RA+CD197- TEMRA (p<0.001) compared to patients with a diverse TCR repertoire. TBET, Perforin and Granzyme-B expression were increased in both CD4 and CD8 T cells in patients with a restricted TCR repertoire. Using multivariate analysis, we found that the increase of highly differentiated TEMRA CD8 T cells was associated with 1.96 high risk of kidney dysfunction (p= 0.06). Conclusion: Despite their long-term stable graft function these patients with a restricted TCR Vb repertoire displayed an increased frequency of highly differentiated CD4 and CD8 T memory cells, as well as increased TBET, Perforin, and Granzyme-B expression, all of which are signs normally associated with poor-functioning graft. As a result, highly differentiated T cells may indicate a group of patients who are at-risk of chronic graft dysfunction.