Urinary tract infection (UTI) is one of the most prevalent human bacterial infections. New therapeutic approaches, including vaccination and immunotherapy, are urgently needed to combat the rapid global dissemination of multidrug-resistant uropathogens. Development of therapies is impeded by an incomplete understanding of memory development during UTI. Here, we found that reducing bacterial load early in infection, by reducing the inoculum or with antibiotics after infection, completely abrogated the protective memory response. We observed a mixed T helper (T H ) cell polarization, composed of T H 1, T H 2, and T H 17 T cells, among T cells infiltrating the bladder during primary infection. Thus, we hypothesized that reducing antigen load altered T H cell polarization, leading to poor memory. Unexpectedly, however, T H cell polarization was unchanged in these scenarios. Instead, we uncovered a population of tissue-resident memory (T RM ) T cells that was significantly reduced in the absence of sufficient antigen. Demonstrating that T RM cells are necessary for immune memory, transfer of lymph node– or spleen-derived infection-experienced T cells to naïve animals did not confer protection against infection. Supporting that T RM cells are sufficient to protect against recurrent UTI, animals depleted of systemic T cells, or treated with FTY720 to block memory lymphocyte migration from lymph nodes to infected tissue, were equally protected compared with unmanipulated mice against a second UTI. Thus, we uncovered an unappreciated key role for T RM cells in the memory response to bacterial infection in the bladder mucosa, providing a target for non–antibiotic-based immunotherapy and/or new vaccine strategies to prevent recurrent UTI.

中文翻译：

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组织驻留记忆 T 细胞介导对复发性尿路感染的粘膜免疫

尿路感染 (UTI) 是最普遍的人类细菌感染之一。迫切需要新的治疗方法，包括疫苗接种和免疫疗法，以对抗多重耐药尿路病原体在全球的快速传播。对 UTI 期间记忆发展的不完全理解阻碍了治疗的发展。在这里，我们发现在感染早期通过减少接种量或在感染后使用抗生素来减少细菌负荷，可以完全消除保护性记忆反应。我们观察到一个混合的 T 助手 (TH) 细胞极化，由 T 组成H1、笔H2，和吨H17 个 T 细胞，在原发感染期间浸润膀胱的 T 细胞中。因此，我们假设减少抗原负荷改变了 TH细胞极化，导致记忆力差。然而出乎意料的是，TH在这些情况下，细胞极化没有改变。相反，我们发现了一群组织驻留记忆（TR M) 在没有足够抗原的情况下显着减少的 T 细胞。证明TR M细胞是免疫记忆所必需的，将淋巴结或脾脏来源的感染经历过的 T 细胞转移给幼稚动物并不能提供抗感染保护。支持那个TR M细胞足以防止复发性 UTI，耗尽全身性 T 细胞或用 FTY720 治疗以阻止记忆淋巴细胞从淋巴结迁移到受感染组织的动物与未处理的小鼠相比对第二次 UTI 具有同等保护。因此，我们发现了 T 的一个未被重视的关键角色R M记忆中的细胞对膀胱粘膜中的细菌感染作出反应，为基于非抗生素的免疫疗法和/或预防复发性 UTI 的新疫苗策略提供了目标。