Exhaustion of CD8^pos central memory regulatory T cell differentiation is involved in renal allograft rejection

The role of regulatory CD8^pos T cells (CD8^pos Tregs) and cytotoxic CD8^pos responder T cells (CD8^pos Tresps) in maintaining stable graft function in kidney transplant recipients (KTR) remains largely unclear. The pathogenesis of graft deterioration in case of rejection involves the exhaustive differentiation of both CD8^pos T cell subsets, but the causal mechanisms have not yet been identified.

In this study, we separately investigated the differentiation of CD8^posTregs/Tresps in 134 stable KTR with no evidence of renal graft rejection, in 41 KTR diagnosed with biopsy-confirmed rejection at enrolment and in 5 patients who were unremarkable at enrolment, but developed rejection within three years of enrolment. We were investigating whether changed differentiation of CCR7^posCD45RA^posCD31^pos recent thymic emigrant (RTE) cells via CD45RA^negCD31^pos memory (CD31^pos memory) cells (pathway 1), via direct proliferation (pathway 2), or via CCR7^posCD45RA⁺CD31^neg resting mature naïve (MN) cells (pathway 3) into CD45RA^negCD31^neg memory (CD31^neg memory) cells affects the CD8^pos Treg/Tresp ratio or identifies a CD8^pos Treg/Tresp subset that predicts or confirms renal allograft rejection.

We found that RTE Treg differentiation via pathway 1 was age-independently increased in KTR, who developed graft rejection during the follow-up period, leading to abundant MN Treg and central memory Treg (CM Treg) production and favoring a strongly increased CD8^pos Treg/Tresp ratio. In KTR with biopsy-confirmed rejection at the time of enrolment, an increased differentiation of RTE Tregs into CCR7^negCD45RA^posCD31^neg terminally differentiated effector memory (CD31^neg TEMRA Tregs) and CD31^pos memory Tregs was observed. CD31^neg memory Treg production was maintained by alternative differentiation of resting MN Tregs, resulting in increased effector memory Treg (EM Treg) production, while the CD8^pos Treg/Treg ratio was unaffected. An altered differentiation of CD8^pos Tresps was not observed, shifting the Treg/Tresp ratio in favor of Tregs.

Our results show that exhaustive CD8^pos Treg differentiation into CM Tregs may lead to future rejection, with a shift towards EM Treg production and an accumulation of CD31^neg TEMRA Tregs in KTR with current rejection.