在一项肺移植受者的纵向研究队列中，交叉反应性 EBV 特异性 CD8+ T 细胞的数量和功能多样性。

Quantitative and functional diversity of cross-reactive EBV-specific CD8+ T cells in a longitudinal study cohort of lung transplant recipients.

机构信息

Department of Medicine, Monash University, Central Clinical School, The Alfred Hospital, Melbourne, Victoria, Australia.

出版信息

Transplantation. 2010 Dec 27;90(12):1439-49. doi: 10.1097/TP.0b013e3181ff4ff3.

DOI:10.1097/TP.0b013e3181ff4ff3

PMID:21042237

Abstract

BACKGROUND

Cross-reactive antiviral memory T cells constitute a significant proportion of the alloresponse, potentially playing a pivotal role in adverse posttransplant outcomes in human leukocyte antigen (HLA)-mismatched allografts. We explored the longitudinal dynamics of cross-reactive HLA-B8-restricted Epstein-Barr virus-specific CD8+ T cells directed toward the EBNA3A epitope FLRGRAYGL (FLR) in lung transplant recipients (LTRs) to determine whether their corecognition of HLA-B*4402 expressed on the allograft contributed to poorer posttransplant outcomes.

METHODS

Cross-reactive FLR-specific CD8+ T cells were measured in the peripheral blood mononuclear cells and bronchoalveolar lavage fluid in 11 HLA-B8+ LTR, who had received HLA-B44+ lung allograft, after in vitro autologous (FLR pulsed) or allogeneic stimulation by multiparameter flow cytometry.

RESULTS

FLR-specific CD8+ T cells were detectable ex vivo and after 13 days following in vitro peptide stimulation of peripheral blood mononuclear cells. Individual LTR and demonstrated diverse functional profiles of either cytokine production and/or cytotoxic potential (interferon-g+, interferon-g+CD107a+ and CD107a+ subsets). However, cells isolated from bronchoalveolar lavage exhibited a skewed functional phenotype toward CD107a expression alone, indicating cytotoxic-producing but not cytokine-producing capabilities. In addition, our findings suggested that the presence of cross-reactive FLR-specific CD8+ T cells may influence the alloreactive hierarchy directed against the allograft, although they were not associated with poorer short- or long-term clinical outcomes in the absence of Epstein-Barr virus reactivation and in the setting of current immunosuppression and antiviral prophylaxis protocols.

CONCLUSION

We report, for the first time, the longitudinal measurement of cross-reactive FLR-specific CD8 T cells within a clinical transplantation framework.

摘要

背景

交叉反应性抗病毒记忆 T 细胞构成同种异体反应的重要组成部分，可能在人类白细胞抗原（HLA）错配同种异体移植物中发挥关键作用，导致不良的移植后结局。我们探索了肺移植受者（LTR）中 HLA-B8 限制性 EBV 特异性 CD8+T 细胞对 EBNA3A 表位 FLRGRAYGL（FLR）的交叉反应性的纵向动力学，以确定其对同种异体移植物上表达的 HLA-B*4402 的共识别是否导致移植后结局更差。

方法

在 11 名 HLA-B8+LTR 中，通过多参数流式细胞术，体外自体（FLR 脉冲）或同种异体刺激后，在其外周血单核细胞和支气管肺泡灌洗液中测量 HLA-B44+肺同种异体移植后交叉反应性的 FLR 特异性 CD8+T 细胞。

结果

在体外肽刺激外周血单核细胞 13 天后，可在外周血中检测到 FLR 特异性 CD8+T 细胞。个体 LTR 表现出不同的功能特征，包括细胞因子产生和/或细胞毒性潜力（干扰素-g+、干扰素-g+CD107a+和 CD107a+亚群）。然而，从支气管肺泡灌洗液中分离出的细胞表现出偏向于 CD107a 表达的功能表型，表明具有细胞毒性产生但无细胞因子产生的能力。此外，我们的研究结果表明，交叉反应性 FLR 特异性 CD8+T 细胞的存在可能影响针对同种异体移植物的同种异体反应性层次，但在没有 EBV 再激活的情况下，并且在当前免疫抑制和抗病毒预防方案的背景下，它们与短期或长期临床结局较差无关。