Immune Regulation In Toxoplasmosis And Other Opportunistic Infections

弓形虫病和其他机会性感染的免疫调节

• 批准号: 7592173
• 负责人: Alan Sher
• 金额: $ 299.86万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592173
• 关键词: Acute; Animals; Annual Reports; Antigen Presentation; Antigen-Presenting Cells; Antigens; Attenuated; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Fraction; Cell physiology; Cells; Complement; Dendritic Cells; Disease; Effector Cell; Frequencies; Genus Mycobacterium; Growth; HIV-1; Healed; Histocompatibility Antigens Class I; Host resistance; Human; Immune; Immune response; Immunity; Immunocompetent; Immunocompromised Host; In Vitro; Individual; Infection; Inflammation; Inflammatory; Interferon Type II; Interleukin-10; Interleukin-12; Interphase Cell; Kinetics; Leishmania major; Mediating; Mus; Natural Killer Cells; Numbers; Opportunistic Infections; Parasites; Pathway interactions; Play; Population; Predisposition; Process; Production; Regulation; Relative (related person); Reporting; Resistance; Role; Source; T-Cell Activation; T-Lymphocyte; Th1 Cells; Time; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Vaccinated; Wild Type Mouse; antigenic peptide transporter; design; healing; imprint; in vivo; killings; macrophage; pathogen; research study; response

In last year's report we described experiments investigating the mechanism of antigen presentation by Toxoplasma infected dendritic cells to CD8+T cells. In these studies T cell activation was shown to be dependent on Transporter Associated with Antigen Processing (TAP)-1 which helps load antigen fragments on to class I MHC molecules in DC. To investigate if TAP-1 is required for CD8+ T cell mediated control of Toxoplasma gondii in vivo, we this year compared the resistance of TAP-1-/-, CD8-/- and wild-type (WT) mice to infection with the parasite. As expected, both TAP-1-/- and CD8-/- animals vaccinated with an attenuated strain of T. gondii failed to develop protective immunity to lethal tachyzoite challenge consistent with absence of effector CD8+ T cells. Surprisingly, TAP-1-/- mice displayed greater susceptibility than CD8-/-, beta2-microglobulin-/- or WT mice to infection with an avirulent parasite strain. The decreased resistance of the TAP-1-/- mice correlated with a reduction in the frequency of activated (CD62Llow CD44hi) and interferon-gamma (IFN-g) producing CD4+ T cells. Interestingly, infected TAP-1-/- mice also showed reduced numbers of IFN-g producing natural killer (NK) cells relative to WT, CD8-/- or beta2-microglobulin-/- mice, and after NK cell-depletion both CD8-/- and WT mice succumbed to infection with the same kinetics as TAP-1-/- animals and displayed impaired CD4+T cell IFN-g responses. These results reveal a role for TAP-1 in the induction of IFN-g producing NK cells and provide the first demonstration of the function of this cell population in the priming of CD4+ T lymphocyte responses to T. gondii infection. In a related project we examined the source of the Interleukin-10 (IL-10) that protects Toxoplasma infected mice from uncontrolled inflammation resulting from the strong Th1 elicited during acute infection.Unexpectedly,IFN-g secreting T-bet+Foxp3- T helper type 1 (Th1) cells were found to be the major producers of IL-10 in these animals rather than Foxp3+ T regulatory cells (Treg) as expected from studies on other T cell derived IL-10 responses. Further analysis revealed that this IL-10+IFN-g+ population paradoxically displays potent effector function against the parasite as evidenced by its ability to trigger intracellular parasite killing in macrophages. Nevertheless the same T lymphocyte population also induced profound suppression of IL-12 production by antigen-presenting cells indicating their dual function as suppressor/effector cells. Although at any given time point only a fraction of the cells appeared to simultaneously produce IL-10 and IFN-g, IL-10 production could be stimulated in IL-10-IFN-g+ cells by further activation in vitro. In addition, experiments with T. gondii specific IL-10+IFN-g+ CD4 clones revealed that although IFN-g expression is imprinted and triggered with similar kinetics regardless of the state of Th1 cell activation, IL-10 secretion is induced more rapidly from recently activated than from resting cells. These findings indicate that IL-10 production by CD4+ T lymphocytes need not involve a distinct regulatory Th cell subset but can be generated in Th1 cells as part of the effector response to intracellular pathogens. They complement parallel studies from Anderson and Sacks in the LPD indicating that the induction of IL-10 producing Th1 cells plays a major role in promoting the growth of non-healing strains of Leishmania major (see Annual Report of D. Sacks).

在去年的报告中，我们描述了研究了弓形虫感染的树突状细胞对CD8+T细胞的抗原表现机制的实验。在这些研究中，T细胞激活显示取决于与抗原加工（TAP）-1相关的转运蛋白，该转运蛋白有助于将抗原片段加载到DC中的I类MHC分子上。为了研究体内CD8+ T细胞介导的弓形虫弓形虫的控制是否需要TAP-1，我们今年比较了TAP-1 - / - ，CD8 - / - 和野生型（WT）小鼠的抗性与寄生虫感染。 如预期的那样，用gondii的衰减菌株疫苗接种的TAP-1 - / - 和CD8 - / - 动物都无法开发出对致命的tachyzoite挑战的保护性免疫，与缺乏效应子CD8+ T细胞一致。令人惊讶的是，TAP-1 - / - 小鼠的敏感性比CD8 - / - ，beta2-microglobolin - / - 或WT小鼠伴有无毒寄生虫菌株感染。 TAP-1 - / - 小鼠的电阻降低与激活（CD62LLOW CD44HI）和产生CD4+ T细胞的干扰素 - γ（IFN-G）的频率的降低相关。 Interestingly, infected TAP-1-/- mice also showed reduced numbers of IFN-g producing natural killer (NK) cells relative to WT, CD8-/- or beta2-microglobulin-/- mice, and after NK cell-depletion both CD8-/- and WT mice succumbed to infection with the same kinetics as TAP-1-/- animals and displayed impaired CD4+T cell IFN-g responses. 这些结果揭示了TAP-1在诱导IFN-G产生NK细胞中的作用，并在CD4+ T淋巴细胞对T. gondii感染的CD4+ T淋巴细胞反应中首次证明了该细胞种群的功能。 在一个相关项目中，我们检查了毒urekin-10（IL-10）的来源，该介绍性的小鼠免受因急性感染期间引起的强th1引起的强烈TH1引起的不受控制的炎症。不预计，IFN-G smitted T-g spectity T-bet+ foxp3- t-t helper type 1（th1）细胞（Th1）细胞是动物的主要生产者。从对其他T细胞得出的IL-10响应的研究预期。进一步的分析表明，该IL-10+ IFN-G+种群矛盾地显示出对寄生虫的有效效应子功能，这证明了其在巨噬细胞中触发细胞内寄生虫杀死的能力。然而，相同的T淋巴细胞种群还通过抗原呈递细胞对IL-12产生的深刻抑制作用，表明其双重功能是抑制器/效应细胞。尽管在任何给定的时间点，只有一小部分细胞似乎同时产生IL-10和IFN-G，但通过进一步激活体外激活，可以在IL-10-IFN-G+细胞中刺激IL-10的产生。此外，使用T. gondii特异性IL-10+ IFN-G+ CD4克隆的实验表明，尽管IFN-G表达是烙印并用相似动力学触发的，无论Th1细胞激活的状态如何，但与最近激活相比，IL-10分泌的诱导更快。这些发现表明，CD4+ T淋巴细胞产生的IL-10不需要涉及不同的调节性TH细胞子集，而是在TH1细胞中生成的，作为对细胞内病原体效应子响应的一部分。它们补充了Anderson和LPD中的麻袋的平行研究，表明产生Th1细胞的IL-10诱导在促进Leishmania Major的非治疗菌株的生长中起着重要作用（请参阅D. Sacks的年度报告）。