Immune Regulation In Toxoplasmosis And Other Opportunistic Infections

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Abstract

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.[unreadable] [unreadable] 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).