CD8 中枢记忆调节性 T 细胞分化耗竭参与肾移植排斥反应。
Exhaustion of CD8 central memory regulatory T cell differentiation is involved in renal allograft rejection.
作者信息
Kälble Florian, Leonhard Jonas, Zeier Martin, Zivanovic Oliver, Schaier Matthias, Steinborn Andrea
机构信息
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
出版信息
Front Immunol. 2025 Jan 24;16:1532086. doi: 10.3389/fimmu.2025.1532086. eCollection 2025.
BACKGROUND
The role of regulatory CD8 T cells (CD8 Tregs) and cytotoxic CD8 responder T cells (CD8 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 T cell subsets, but the causal mechanisms have not yet been identified.
METHODS
In this study, we separately investigated the differentiation of CD8Tregs/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 CCR7CD45RACD31 recent thymic emigrant (RTE) cells via CD45RACD31 memory (CD31 memory) cells (pathway 1), via direct proliferation (pathway 2), or via CCR7CD45RACD31 resting mature naïve (MN) cells (pathway 3) into CD45RACD31 memory (CD31 memory) cells affects the CD8 Treg/Tresp ratio or identifies a CD8 Treg/Tresp subset that predicts or confirms renal allograft rejection.
RESULTS
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 Treg/Tresp ratio. In KTR with biopsy-confirmed rejection at the time of enrolment, an increased differentiation of RTE Tregs into CCR7CD45RACD31 terminally differentiated effector memory (CD31 TEMRA Tregs) and CD31 memory Tregs was observed. CD31 memory Treg production was maintained by alternative differentiation of resting MN Tregs, resulting in increased effector memory Treg (EM Treg) production, while the CD8 Treg/Treg ratio was unaffected. An altered differentiation of CD8 Tresps was not observed, shifting the Treg/Tresp ratio in favor of Tregs.
CONCLUSIONS
Our results show that exhaustive CD8 Treg differentiation into CM Tregs may lead to future rejection, with a shift towards EM Treg production and an accumulation of CD31 TEMRA Tregs in KTR with current rejection.
背景
调节性CD8 T细胞（CD8 Tregs）和细胞毒性CD8应答性T细胞（CD8 Tresps）在维持肾移植受者（KTR）移植肾功能稳定中的作用仍不清楚。排斥反应时移植物恶化的发病机制涉及这两种CD8 T细胞亚群的耗竭性分化，但因果机制尚未明确。
方法
在本研究中，我们分别调查了134例无肾移植排斥证据的稳定KTR、41例入组时经活检确诊为排斥反应的KTR以及5例入组时无异常但在入组后3年内发生排斥反应的患者中CD8Tregs/Tresps的分化情况。我们研究了通过CD45RACD31记忆（CD31记忆）细胞（途径1）、通过直接增殖（途径2）或通过CCR7CD45RACD31静息成熟幼稚（MN）细胞（途径3）分化为CD45RACD31记忆（CD31记忆）细胞的CCR7CD45RACD31近期胸腺迁出细胞（RTE）的分化变化是否会影响CD8 Treg/Tresp比率，或是否能识别出预测或确认肾移植排斥反应的CD8 Treg/Tresp亚群。
结果
我们发现，在随访期间发生移植物排斥反应的KTR中，通过途径1的RTE Treg分化不受年龄影响而增加，导致大量MN Treg和中枢记忆Treg（CM Treg）产生，并使CD8 Treg/Tresp比率大幅增加。在入组时经活检确诊为排斥反应的KTR中，观察到RTE Tregs向CCR7CD45RACD31终末分化效应记忆（CD31 TEMRA Tregs）和CD31记忆Tregs的分化增加。静息MN Tregs的替代分化维持了CD31记忆Treg的产生，导致效应记忆Treg（EM Treg）产生增加，而CD8 Treg/Treg比率不受影响。未观察到CD8 Tresps的分化改变，使Treg/Tresp比率向有利于Tregs的方向转变。
结论
我们的结果表明，CD8 Tregs向CM Tregs的耗竭性分化可能导致未来的排斥反应，在当前发生排斥反应的KTR中会向EM Treg产生转变，并出现CD31 TEMRA Tregs的积累。
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