Gamma Delta T Cell Recognition in Tularemia

图拉氏方济氏菌在局部感染，然后通过菌血症传播到全身 和/或受感染的巨噬细胞。感染的头几天通常是决定是否 宿主会活下来的。NK细胞和Y5 T处于天然免疫和获得性免疫的交界处 细胞大量存在，并对各种病毒、细菌和 寄生虫。这些“快速反应”淋巴细胞杀死受感染的细胞，分泌大量的干扰素-γ和 刺激受感染的巨噬细胞杀死细胞内细菌的肿瘤坏死因子-a。人V72V52 T细胞扩增 在图拉热病感染期间迅速达到非常高的水平(循环T细胞的22%-50%)，支持他们的 在图拉氏方济氏菌免疫应答中的重要作用。我们已经证明，完全相同的展开 猴子的V？2Vd2 T细胞具有记忆T细胞反应的特征，并且这些扩张是一致的 随着分枝杆菌感染的解决。我们发现V？2Vd2 T细胞利用它们的TCR识别 细菌和原虫对常见微生物代谢中间体(E)-4-反应的感染 羟基-3-甲基-2-烯基焦磷酸酯(HMBPP)。为了支持Y8 T细胞的记忆反应，我们发现 成体V？2Vd2 T细胞几乎完全是记忆细胞，分为3个亚群，中央 内存、效应器内存和效应器CD45RA+内存。我们假设人类的反应 记忆V？2Vd2 T细胞对图拉氏原虫感染细胞表面的磷抗原提供了至关重要的 图拉热症患者T细胞和B细胞反应前的“桥接免疫”。 尽管V？2Vd2 T细胞在人类图拉热症中很重要，但还没有疫苗刺激这种T细胞。 细胞子集。启动或增强V？2Vd2 T细胞记忆应有助于提供早期、部分免疫并将 对图拉热症和其他感染的病原体特异性AP T细胞也有佐剂作用 产生HMBPP的病原体包括炭疽和鼠疫。在这里，我们建议(1)测试V？2Vd2 T细胞 对图拉氏丝虫感染细胞的识别，(2)确定V？2Vd2 T细胞对T细胞存活的贡献 感染图拉氏丝虫的人PBMC-SCID-Beige小鼠，(3)获得V？2Vd2T活细菌疫苗 从减毒沙门氏菌中过度生产HMBPP的细胞，以及(4)测试HMBPP/佐剂疫苗和活着 细菌疫苗能够刺激猴子的V？2Vd2 T细胞免疫。这些研究将 阐明V？2Vd2 T细胞在兔热病中的关键作用，并将开发针对V？2Vd2 T细胞的疫苗。

Francisella tularensis infects at local sites before being disseminated throughout the body via bacteremia and/or infected macrophages. The first few days of infection are often critical in determining whether or not the host will survive. Positioned at the interface between innate and adaptive immunity, NK cells and y5 T cells are present in large numbers and respond rapidly to infection by a variety of viruses, bacteria, and parasites. These "rapid response" lymphocytes kill infected cells and.secrete large amounts of IFN-y and TNF-a that stimulate infected macrophages to kill intracellular bacteria. Human V72V52 T cells expand rapidly during tularemia infections to very high levels (22-50% of circulating T cells) supporting their important role in the immune response to Francisella tularensis. We have shown that identical expansions of monkey V?2Vd2 T cells have characteristics of memory T cell responses and that these expansions coincide with the resolution of mycobacterial infections. We find that V?2Vd2 T cells use their TCRs to recognize bacterial and protozoal infections by responding to a common microbial metabolic intermediate, (E)-4- hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). In support of memory responses by y8 T cells, we find that adult V?2Vd2 T cells are almost exclusively memory cells that are divided into 3 subsets, central memory, effector memory, and effector CD45RA+ memory. We hypothesize that the response of human memory V?2Vd2 T cells to phosphoantigens on the surface of F. tularensis infected cells provides vital bridge immunity" in tularemia before a¿ T cell and B cell responses. Despite the importance of V?2Vd2 T cells in human tularemia there are no vaccines that stimulate this T cell subset. Priming or boosting V?2Vd2 T cell memory should help provide early, partial immunity and will also have an adjuvant effects on pathogen-specific ap T cells for tularemia and for other infections with pathogens that produce HMBPP including anthrax and plague. Here we propose to (1) test V?2Vd2 T cell ¿ecognition of F. tularensis infected cells, (2) determine the contribution of V?2Vd2 T cell to the survival of human PBMC-SCID-beige mice infected with F. tularensis, (3) derive live bacterial vaccines for V?2Vd2 T ells that overproduce HMBPP from attenuated Salmonella, and (4) test HMBPP/adjuvant vaccines and live bacterial vaccines for their ability to stimulate V?2Vd2 T cell immunity in monkeys. These studies will lucidate the critical role of V?2Vd2 T cells in tularemia and will develop vaccines that target V?2Vd2 T cells.