Polyfunctional T Cell Responses in Children in Early Stages of Chronic Trypanosoma cruzi Infection Contrast with Monofunctional Responses of Long-term Infected Adults

BackgroundAdults with chronic Trypanosoma cruzi exhibit a poorly functional T cell compartment, characterized by monofunctional (IFN-γ-only secreting) parasite-specific T cells and increased levels of terminally differentiated T cells. It is possible that persistent infection and/or sustained exposure to parasites antigens may lead to a progressive loss of function of the immune T cells.Methodology/Principal FindingsTo test this hypothesis, the quality and magnitude of T. cruzi-specific T cell responses were evaluated in T. cruzi-infected children and compared with long-term T. cruzi-infected adults with no evidence of heart failure. The phenotype of CD4+ T cells was also assessed in T. cruzi-infected children and uninfected controls. Simultaneous secretion of IFN-γ and IL-2 measured by ELISPOT assays in response to T. cruzi antigens was prevalent among T. cruzi-infected children. Flow cytometric analysis of co-expression profiles of CD4+ T cells with the ability to produce IFN-γ, TNF-α, or to express the co-stimulatory molecule CD154 in response to T. cruzi showed polyfunctional T cell responses in most T. cruzi-infected children. Monofunctional T cell responses and an absence of CD4+TNF-α+-secreting T cells were observed in T. cruzi-infected adults. A relatively high degree of activation and differentiation of CD4+ T cells was evident in T. cruzi-infected children.Conclusions/SignificanceOur observations are compatible with our initial hypothesis that persistent T. cruzi infection promotes eventual exhaustion of immune system, which might contribute to disease progression in long-term infected subjects.

研究背景 慢性克氏锥虫（Trypanosoma cruzi）感染者的T细胞室功能低下，其特征为仅分泌干扰素-γ（IFN-γ）的单功能性寄生虫特异性T细胞，以及终末分化T细胞水平升高。持续感染或长期暴露于寄生虫抗原，可能会导致免疫T细胞功能进行性丧失。

研究方法与主要结果 为验证上述假说，本研究对克氏锥虫感染儿童体内的克氏锥虫特异性T细胞应答的质量与强度进行了评估，并与无心力衰竭证据的长期克氏锥虫感染成人进行对比。同时，本研究还对克氏锥虫感染儿童及未感染对照人群的CD4阳性T细胞（CD4+ T细胞）表型进行了分析。针对克氏锥虫抗原的干扰素-γ与白细胞介素-2（IL-2）联合分泌现象在克氏锥虫感染儿童中较为普遍，该结果通过酶联免疫斑点试验（ELISPOT）得以检测。针对克氏锥虫抗原、可产生干扰素-γ、肿瘤坏死因子-α（TNF-α）或表达共刺激分子CD154的CD4阳性T细胞的共表达谱进行流式细胞术分析后发现，多数克氏锥虫感染儿童呈现多功能性T细胞应答。而克氏锥虫感染成人仅观察到单功能性T细胞应答，且不存在分泌肿瘤坏死因子-α的CD4阳性T细胞群体。此外，克氏锥虫感染儿童的CD4阳性T细胞呈现较高程度的活化与分化状态。

结论与意义 本研究结果与初始假说一致：持续的克氏锥虫感染会最终导致免疫系统耗竭，这可能会促进长期感染个体的疾病进展。