Numerous epidemiological and clinical studies have noted differences in the incidence and severity of parasitic diseases between males and females. Although in some instances this may be due to gender-associated differences in behavior, there is overwhelming evidence that sex-associated hormones can also modulate immune responses and consequently directly influence the outcome of parasitic infection. Animal models of disease can often recreate the gender-dependent differences observed in humans, and the role of sex-associated hormones can be confirmed by experimentally altering their levels. Under normal circumstances, levels of sex hormones not only differ between males and females but vary according to age. Furthermore, not only are females of reproductive age subject to the regular hormonal cycles which control ovulation, they are also exposed to dramatically altered levels during pregnancy. It is thus not surprising that the severity of many diseases, including those caused by parasites, has been shown to be affected by one or more of these circumstances. In addition, infection with many pathogens has been shown to have an adverse influence on pregnancy. In this article we review the impact of sex-associated hormones on the immune system and the development and maintenance of immunity to the intracellular protozoan parasites Toxoplasma gondii, Plasmodium spp., and Leishmania spp

Parasitic protozoa of the genus Leishmania have provided a useful perspective for immunologists in terms of host defense mechanisms critical for the resolution of infection caused by intracellular pathogens. These organisms, which normally reside in a late endosomal, major histocompatibility complex (MHC) class II(+) compartment within host macrophages cells, require CD4(+) T-cell responses for the control of disease. The paradigm for the CD4(+) T-helper 1 (Th1)/Th2 dichotomy is largely based on the curing/non-curing responses, respectively, to Leishmania major infection. However, this genus of parasitic protozoa is evolutionarily diverse, with the cutaneous disease-causing organisms of the Old World (L. major) and New World (Leishmania mexicana/ Leishmania amazonensis) having diverged 40-80 million years ago. Further adaptations to survive within the visceral organs (for Leishmania donovani, Leishmania chagasi, and Leishmania infantum) must have been required. Consequently, significant differences in host-parasite interactions have evolved. Different virulence factors have been identified for distinct Leishmania species, and there are profound differences in the immune mechanisms that mediate susceptibility/resistance to infection and in the pathology associated with disease. These variations not only point to interesting features of the host-pathogen interaction and immunobiology of this genus of parasitic protozoa, but also have important implications for immunotherapy and vaccine development.

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CD8(+) T cells are essential for long-term, vaccine-induced resistance against intracellular pathogens. Here we show that natural antibodies, acting in concert with complement, are endogenous adjuvants for the generation of protective CD8(+) T cells after vaccination against visceral leishmaniasis. IL-4 was crucial for the priming of vaccine-specific CD8(+) T cells, and we defined the primary source of IL-4 as a CD11b(+)CD11c(lo) phagocyte. IL-4 secretion was not observed in antibody-deficient mice and could be reconstituted with serum from normal, but not Btk immune-deficient, mice. Similarly, no IL-4 response or CD8(+) T-cell priming was seen in C1qa(-/-) mice. These results identify a new pathway by which immune complex-mediated complement activation can regulate T-cell-mediated immunity. We propose that this function of natural antibodies could be exploited when developing new vaccines for infectious diseases.

Regulatory T cells play a major role in modulating the immune response. However, most information on these cells centers on autoimmunity, and there is also considerable controversy on the functional characteristics of these cells. Here we provide direct in vitro and in vivo evidence that CD4+CD25+ regulatory T cells inhibit the differentiation and functions of both Th1 and Th2 cells. Importantly, CD4+CD25+ T cells suppressed the disease development of Leishmania major infection in SCID mice reconstituted with naive CD4+CD25− T cells. Furthermore, CD4+CD25+ T cells inhibited the development of colitis induced by both Th1 and Th2 cells in SCID mice. Our results therefore document that CD4+CD25+ regulatory T cells suppress both Th1 and Th2 cells and that these regulatory T cells have a profound therapeutic potential against diseases induced by both Th1 and Th2 cells in vivo.

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