DataSheet_1_Filarial Lymphedema Patients Are Characterized by Exhausted CD4+ T Cells.docx

Worldwide, more than 200 million people are infected with filariae which can cause severe symptoms leading to reduced quality of life and contribute to disability-adjusted life years (DALYs). In particular, lymphatic filariasis (LF) caused by Wuchereria bancrofti can lead to lymphedema (LE) and consequently presents a serious health problem. To understand why only a fraction of the infected individuals develop pathology, it is essential to understand how filariae regulate host immunity. The central role of T cells for immunity against filariae has been shown in several studies. However, there is little knowledge about T cell exhaustion, which causes T cell dysfunction and impaired immune responses, in this group of individuals. Recently, we showed that LE patients from Ghana harbor distinct patterns of exhausted effector and memory CD8+ T cell subsets. Based on these findings, we now characterized CD4+ T cell subsets from the same Ghanaian patient cohort by analyzing distinct markers within a 13-colour flow cytometry panel. We revealed that LE patients had increased frequencies of CD4+ T cells expressing exhaustion-associated receptors such as KLRG-1, TIM-3 and PD-1 compared to healthy endemic normal and W. bancrofti-infected individuals. Moreover, CD4+ T cells in LE patients were characterized by distinct co-expression patterns of inhibitory receptors. Collectively with the previous findings on CD8+ T cell exhaustion patterns, the data shown here demonstrates that filarial LE patients harbor distinct subsets of exhausted T cells. Thus, T cell exhaustion patterns in LE patients need attention especially in regards to susceptibility of concomitant infections and should be taken into consideration for LE management measures.

全球范围内，超过2亿人感染丝虫（filariae），该感染可引发严重症状，导致生活质量下降并增加伤残调整寿命年（disability-adjusted life years, DALYs）的负担。尤其由班氏吴策线虫（Wuchereria bancrofti）引发的淋巴丝虫病（lymphatic filariasis, LF）可导致淋巴水肿（lymphedema, LE），因此成为严重的公共卫生问题。为明确为何仅部分感染者会出现病理症状，解析丝虫如何调控宿主免疫至关重要。多项研究已证实T细胞在抗丝虫免疫中的核心作用，但目前针对这类人群中引发T细胞功能障碍与免疫应答受损的T细胞耗竭（T cell exhaustion）认知仍十分有限。近期我们的研究发现，来自加纳的淋巴水肿患者存在独特的耗竭效应性与记忆性CD8+ T细胞亚群特征。基于上述发现，本研究通过13色流式细胞术检测组合分析特定标志物，对同一加纳患者队列的CD4+ T细胞亚群进行了表征。结果显示，与健康流行区对照人群及班氏吴策线虫感染者相比，淋巴水肿患者体内表达KLRG-1、TIM-3、PD-1等耗竭相关受体的CD4+ T细胞频率显著升高。此外，淋巴水肿患者的CD4+ T细胞还呈现出独特的抑制性受体共表达模式。结合此前关于CD8+ T细胞耗竭特征的研究发现，本研究数据证实丝虫病相关淋巴水肿患者存在独特的耗竭T细胞亚群。因此，淋巴水肿患者的T细胞耗竭特征需得到关注，尤其是在合并感染易感性方面，且该特征应纳入淋巴水肿的管理策略中。