Selective CD28 blockade impacts T cell differentiation during homeostatic reconstitution following lymphodepletion.
Selective CD28 blockade impacts T cell differentiation during homeostatic reconstitution following lymphodepletion.
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DOI：
10.3389/fimmu.2022.1081163
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发表时间：
2022
影响因子：
7.3
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中科院分区：
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与钙调磷酸酶抑制剂相比，靶向CD 28通路的共刺激阻断剂提供了改善的长期肾同种异体移植物存活率，但可能受到限制，因为CTLA-4-IG（阿巴西普，贝拉西普）阻断了CD 28共刺激和CTLA-4共抑制。直接靶向CD 28同时保持CTLA-4完整可以提供机制优势。Fc沉默的非交联CD 28拮抗结构域抗体（dAb）目前处于肾移植的临床试验中。考虑到目前美国大部分中心肾移植的护理标准，通过胸腺球蛋白诱导治疗的淋巴细胞清除可能用于接受CD 28拮抗剂治疗的患者。因此，我们研究了T细胞耗竭（TCD）对T细胞表型的影响后，在小鼠模型的皮肤移植用抗CD 28 dAb治疗的稳态重建。将BALB/cJ供体的皮肤移植到C56 BL/6受体上，受体在移植前1天用或不用0.2mg抗CD 4和10μg抗CD 8治疗，在第0、2、4、6天用或不用100μg抗CD 28 dAb治疗，此后每周一次。移植后6周将小鼠安乐死，并通过流式细胞术分析淋巴细胞。与单独的TCD相比，抗CD 28 dAb逆转了脾和淋巴结中淋巴细胞减少诱导的记忆性CD 4 + T细胞的分化。与单独抗CD 28 dAb相比，经TCD+抗CD 28 dAb治疗的小鼠表现出显著改善的皮肤移植物存活率，与未治疗相比也有所改善。此外，与单用TCD相比，接受TCD+抗CD 28 dAb的小鼠脾脏和淋巴结中CD 4+和CD 8 + T细胞上CD 69的表达降低。虽然相对于未处理的对照，在抗CD 28 dAb处理的小鼠中观察到CD 4 + FoxP 3 + T细胞的频率降低，但与单独给予TCD相比，在给予TCD+抗CD 28 dAb的小鼠的血液和肾脏中观察到的CD 8 + Foxp 3 + T细胞的频率增加，从而平衡了这一点。这些数据表明，CD 28信号传导影响淋巴细胞耗竭后稳态重建期间CD 4+和CD 8 + T细胞的分化，导致向更少的活化记忆T细胞和更多的CD 8 + FoxP 3 + T细胞转变，这可能是观察到的同种异体移植物存活延长的基础。
Costimulation blockade targeting the CD28 pathway provides improved long-term renal allograft survival compared to calcineurin inhibitors but may be limited as CTLA-4-Ig (abatacept, belatacept) blocks both CD28 costimulation and CTLA-4 coinhibition. Directly targeting CD28 while leaving CTLA-4 intact may provide a mechanistic advantage. Fc-silent non-crosslinking CD28 antagonizing domain antibodies (dAb) are currently in clinical trials for renal transplantation. Given the current standard of care in renal transplantation at most US centers, it is likely that lymphodepletion via thymoglobulin induction therapy could be used in patients treated with CD28 antagonists. Thus, we investigated the impact of T cell depletion (TCD) on T cell phenotype following homeostatic reconstitution in a murine model of skin transplantation treated with anti-CD28dAb. Skin from BALB/cJ donors was grafted onto C56BL/6 recipients which were treated with or without 0.2mg anti-CD4 and 10μg anti-CD8 one day prior to transplant and with or without 100μg anti-CD28dAb on days 0, 2, 4, 6, and weekly thereafter. Mice were euthanized six weeks post-transplant and lymphoid cells were analyzed by flow cytometry. Anti-CD28dAb reversed lymphopenia-induced differentiation of memory CD4+ T cells in the spleen and lymph node compared to TCD alone. Mice treated with TCD+anti-CD28dAb exhibited significantly improved skin graft survival compared to anti-CD28dAb alone, which was also improved compared to no treatment. In addition, the expression of CD69 was reduced on CD4+ and CD8+ T cells in the spleen and lymph node from mice that received TCD+anti-CD28dAb compared to TCD alone. While a reduced frequency of CD4+FoxP3+ T cells was observed in anti-CD28dAb treated mice relative to untreated controls, this was balanced by an increased frequency of CD8+Foxp3+ T cells that was observed in the blood and kidney of mice given TCD+anti-CD28dAb compared to TCD alone. These data demonstrate that CD28 signaling impacts the differentiation of both CD4+ and CD8+ T cells during homeostatic reconstitution following lymphodepletion, resulting in a shift towards fewer activated memory T cells and more CD8+FoxP3+ T cells, a profile that may underpin the observed prolongation in allograft survival.