Clinical significance of CD161⁺CD4⁺ T cells in the development of chronic antibody-mediated rejection in kidney transplant recipients

In this study, we investigated whether CD161⁺CD4⁺ T cells can reflect the Th17 pathway in kidney transplant recipients (KTRs) and investigated the clinical significance of this cell type in chronic antibody-mediated rejection (cAMR) in KT. First, we investigated the relationship between CD161⁺CD4⁺ T and Th17 cells by flow cytometry and microarray analysis in an in vitro study. Second, we compared the proportion of T cell subsets including CD161⁺CD4⁺ T cells in cAMR (n = 18), long-term graft survival (LTGS) (n = 46), and interstitial fibrosis/tubular atrophy (IF/TA) (n = 22). We compared CD161⁺ cell infiltration between cAMR and IF/TA and also examined the effect of CD161⁺ T cells on human renal proximal tubular epithelial cells (HRPTEpiC). In flow cytometry, the proportion of CD161⁺CD4⁺ T cells showed a significant correlation with the proportion of Th17 cells. In microarray analysis, transcripts associated with the Th17 pathway such as IL18RAP, IL-18R1, IL23R, IL12RB2, RORC, TBX21, and EOMES were upregulated in CD161⁺ cells compared with CD161^- cells. In an ex vivo study, only CD161⁺CD4⁺ T cells showed a significant increase in the cAMR group compared with IF/TA and LTGS groups. In allograft tissue, CD161⁺ cells showed a higher level of infiltration in the cAMR group than the IF/TA group. Lastly, CD161⁺ T cells increased the production of inflammatory cytokines from HRPTEpiC in a dose-dependent manner. This study suggests that monitoring of CD161⁺ T cells can be useful to detect the progression of cAMR.