Chronic Parasitic Infection Maintains High Frequencies of Short-Lived Ly6C+CD4+ Effector T Cells That Are Required for Protection against Re-infection

In contrast to the ability of long-lived CD8+ memory T cells to mediate protection against systemic viral infections, the relationship between CD4+ T cell memory and acquired resistance against infectious pathogens remains poorly defined. This is especially true for T helper 1 (Th1) concomitant immunity, in which protection against reinfection coincides with a persisting primary infection. In these situations, pre-existing effector CD4 T cells generated by ongoing chronic infection, not memory cells, may be essential for protection against reinfection. We present a systematic study of the tissue homing properties, functionality, and life span of subsets of memory and effector CD4 T cells activated in the setting of chronic Leishmania major infection in resistant C57Bl/6 mice. We found that pre-existing, CD44+CD62L−T-bet+Ly6C+ effector (TEFF) cells that are short-lived in the absence of infection and are not derived from memory cells reactivated by secondary challenge, mediate concomitant immunity. Upon adoptive transfer and challenge, non-dividing Ly6C+ TEFF cells preferentially homed to the skin, released IFN-γ, and conferred protection as compared to CD44+CD62L−Ly6C− effector memory or CD44+CD62L+Ly6C− central memory cells. During chronic infection, Ly6C+ TEFF cells were maintained at high frequencies via reactivation of TCM and the TEFF themselves. The lack of effective vaccines for many chronic diseases may be because protection against infectious challenge requires the maintenance of pre-existing TEFF cells, and is therefore not amenable to conventional, memory inducing, vaccination strategies.与长寿CD8+记忆T细胞（CD8+ memory T cells）介导系统性病毒感染防护的功能相比，CD4+ T细胞记忆与获得性抗病原体感染抵抗力之间的关联仍未得到充分阐明。这一情况在T辅助1（Th1，T helper 1）伴随免疫中尤为突出，此类免疫中抗再感染的保护作用与持续性原发感染相伴而生。在此类情境下，由持续慢性感染诱导产生的预存效应CD4 T细胞（而非记忆细胞），或许是抵御再感染的关键要素。本研究针对抗性品系C57BL/6小鼠（C57Bl/6 mice）中，因硕大利什曼原虫（Leishmania major）慢性感染而活化的记忆与效应CD4 T细胞亚群的组织归巢特性、功能及存活时长展开了系统性研究。研究发现，预存的CD44+CD62L−T-bet+Ly6C+效应（TEFF，effector T）细胞——这类细胞在无感染状态下寿命较短，且并非由二次攻击活化的记忆细胞衍生而来——可介导伴随免疫。过继转移并攻击感染后，与CD44+CD62L−Ly6C−效应记忆细胞或CD44+CD62L+Ly6C−中央记忆（TCM，central memory T）细胞相比，非增殖性Ly6C+ TEFF细胞更倾向于归巢至皮肤，分泌干扰素-γ（IFN-γ）并赋予宿主防护能力。在慢性感染过程中，Ly6C+ TEFF细胞可通过中央记忆T细胞（TCM）以及TEFF细胞自身的再活化，维持较高的细胞比例。诸多慢性疾病至今缺乏有效疫苗，其原因可能在于抵御感染攻击的防护需要维持预存的TEFF细胞，因此无法适配常规的诱导记忆型疫苗接种策略。