Attenuated Oral Typhoid Vaccine Ty21a Elicits Lamina Propria and Intra-Epithelial Lymphocyte Tissue-Resident Effector Memory CD8T Responses in the Human Terminal Ileum
Attenuated Oral Typhoid Vaccine Ty21a Elicits Lamina Propria and Intra-Epithelial Lymphocyte Tissue-Resident Effector Memory CD8T Responses in the Human Terminal Ileum
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DOI：
10.3389/fimmu.2019.00424
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发表时间：
2019-03-14
影响因子：
7.3
通讯作者：
Sztein, Marcelo B.
中科院分区：
文献类型：
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作者：
Booth, Jayaum S.;Patil, Seema A.;Sztein, Marcelo B.
组织常驻记忆T细胞（T- rm）是一种新定义的记忆T细胞（T- m），不同于循环T- m亚群，具有在感染部位产生快速保护性免疫反应的潜力。然而，关于T-RM在人类感染部位疫苗介导的免疫反应中的作用和贡献的信息非常有限。在本研究中，我们研究了口服Ty21a免疫后，位于回肠末端（伤寒沙门氏菌感染的有利部位）的组织常驻记忆T细胞（T- rm）的作用和贡献。我们检测了从接受医学指示的结肠镜检查的健康志愿者中获得的ti -固有层单个核细胞（LPMC）和上皮内淋巴细胞（IEL） CD8+ T-RM亚群，这些志愿者要么接种了Ty21a，要么未接种疫苗。经ty21a免疫后，LPMC CD8+ T- rm和CD8+CD69+CD103- T细胞亚群的频率无显著差异。然而，与未接种ty21a疫苗的志愿者相比，LPMC CD8+ T-RM在体外表现出更高水平的细胞因子（ifn - γ， IL-17A和tnf - α）。利用斑疹伤寒感染的靶标评估LPMC CD8+ TRM斑疹伤寒特异性应答，发现产生显著更高水平的斑疹伤寒特异性IL-17A。相比之下，LPMC CD8+CD69+CD103- T细胞产生显著增加斑斑病特异性的ifn - γ、IL-2和IL-17A水平。最后，我们对IEL中的CD8+ T-RM进行了评估，发现免疫Ty21a后，IEL CD8+ T（RM）的频率显著降低。然而，Ty21a免疫引起的离体IEL CD8+ T-RM自发产生显著更高水平的细胞因子（ifn - γ、IL-17A、IL-2和tnf - α）。本研究首次证明了口服Ty21a疫苗接种对人回肠末端粘膜LPMC和IEL区CD8+ T（RM）亚群（自发和斑疹伤寒特异性）反应的影响，为我们理解口服Ty21a免疫后粘膜免疫反应的产生提供了新的信息。
Tissue-resident memory T cells (T-RM) are newly defined memory T cells (T-M) distinct from circulating T-M subsets which have the potential to mount rapid protective immune responses at the site of infection. However, very limited information is available regarding the role and contribution of T-RM in vaccine-mediated immune responses in humans at the site of infection. Here, we studied the role and contribution of tissue resident memory T cells (T-RM) located in the terminal ileum (TI) (favored site of infection for S. Typhi) following oral Ty21a immunization in humans. We examined TI-lamina propria mononuclear cells (LPMC) and intra-epithelial lymphocytes (IEL) CD8+ T-RM subsets obtained from healthy volunteers undergoing medically-indicated colonoscopies who were either immunized with Ty21a or unvaccinated. No significant differences in the frequencies of LPMC CD8+ T-RM and CD8+CD69+CD103- T cells subsets were observed following Ty21a-immunization. However, LPMC CD8+ T-RM exhibited significantly higher levels of cytokines (IFN-gamma, IL-17A, and TNF-alpha) ex-vivo in Ty21a-vaccinated than in unvaccinated volunteers. LPMC CD8+ TRM S. Typhi-specific responses were evaluated using S. Typhi-infected targets and found to produce significantly higher levels of S. Typhi-specific IL-17A. In contrast, LPMC CD8+CD69+CD103- T cells produced significantly increased S. Typhi-specific levels of IFN-gamma, IL-2, and IL-17A. Finally, we assessed CD8+ T-RM in IEL and observed that the frequency of IEL CD8+ T(RM )is significantly lower following Ty21a immunization. However, ex-vivo IEL CD8+ T-RM elicited by Ty21a immunization spontaneously produced significantly higher levels of cytokines (IFN-gamma, IL-17A, IL-2, and TNF-alpha). This study provides the first demonstration of the effect of oral Ty21a vaccination on CD8+ T(RM )subsets (spontaneous and S. Typhi-specific) responses in the LPMC and IEL compartment of the human terminal ileum mucosa, contributing novel information to our understanding of the generation of mucosal immune responses following oral Ty21a-immunization.