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Levels of expression of costimulatory molecules have been proposed to influence the outcome of antigen-specific T cell priming. We found that Leishmania major selectively modulated the expression of costimulatory molecules on various populations of epidermal cells. B7.2 expression was down-regulated on Thy1.2+ epidermal cells (keratinocytes) from disease-resistant C3H mice, but not from disease-susceptible BALB/c mice. In addition, epidermal cells from BALB/c mice showed a down-regulation of B7.1 expression on NLDC 145+ Langerhans cells. In vitro T cell priming experiments, using syngeneic epidermal cells as antigen-presenting cells (APC), showed that the production of IFN-gamma was inhibited when either B7.1 or B7.2 signaling pathways were blocked. Blockade of B7.2, but not B7.1, significantly inhibited the ability of epidermal cells to induce IL-4 production from CD4+ T cells. In addition, C3H CD4+ T cells, which were unable to secrete detectable levels of IL-4 in cultures with syngeneic APC, were now able to secrete IL-4 following presentation of L. major antigens by congenic BALB/K epidermal cells. Conversely, C3H epidermal cells supported the priming of BALB/K CD4+ T cells for IL-4 production in vitro. Thus, the differential expression of B7 molecules on epidermal cells may not represent the sole factor governing the polarization of L. major-specific CD4+ T cells in vitro.

Sand fly saliva contains maxadilan, a peptide that causes vasodilation and modifies the secretion of pro-inflammatory cytokines by macrophages. We show that 1 to 10 microg maxadilan protected BALB/c mice against a lethal dose of LPS. Maxadilan reduced serum levels of TNF-alpha by approximately tenfold, while it caused a threefold increase in IL-6 and IL-10. The protective effect of maxadilan is partially dependent on its ability to induce IL-10 production since maxadilan did not prevent death from endotoxic shock in IL-10(-/-) mice. Finally, maxadilan is a selective agonist of the pituitary adenylate cyclase-activating peptide (PACAP) type I receptor, and we found that the natural ligand of this receptor (PACAP 38) also protected mice against lethal endotoxemia. These results indicate that activation of the PACAP type I receptor may contribute to the control of systemic inflammation by a mechanism that is partially dependent on IL-10.

Leishmania major-specific T cell lines were derived from mice sensitized to the parasite. The cells were of the CD4+ T cell lineage and, upon adoptive transfer, were found to be capable of inducing parasite-specific delayed-type hypersensitivity. Adoptive transfer of these L. major-specific T cells to syngeneic recipients which were either normal, T cell deficient or B cell and antibody deficient led to exacerbation of infection upon subsequent challenge with L. major. This suggested that host T cells, B cells and antibody were not required for the L. major-specific T cells to exert their exacerbative effect on the course of cutaneous leishmaniasis. Additional studies revealed that the adoptive transfer of graded doses of these L. major-specific T cells always resulted in exacerbation of infection. Study of the localization pattern of the cells following transfer showed that they migrate preferentially to the site of the lesions. Furthermore, although the induction phase of this phenomenon was immunologically specific, its effector phase was not. Finally, T cell clones were derived from the L. major-specific T cell lines. The T cell clones were phenotypically and functionally identical to the T cell lines from which they were derived. Adoptive transfer of these parasite-specific T cell clones to normal syngeneic recipients induced an exacerbated course of infection with L. major. Interestingly, when these cloned T cells were specifically activated in vitro, the cells produced interleukin 2 and interferon-gamma, but no interleukin 4, indicating that they belong to the murine Th1 subset of CD4+ T cells.

The involvement of Lyt-2+ T cells in the immunological control of cutaneous leishmaniasis was assessed by studying the course of the disease in mice in which the number of these cells was reduced by treatment with anti-Lyt-2 monoclonal antibody (mAb). Administration of anti-Lyt-2 mAb exacerbated Leishmania major-induced cutaneous lesions in both genetically resistant and susceptible mice. This effect correlated with a drastic reduction in the number of specific Lyt-2+ T cells generated during infection. These results, together with the observation that resistant mice possess higher numbers of specific Lyt-2+ T cells in lymph nodes draining their lesions than susceptible mice, 3 weeks after infection, indicate that Lyt-2+ T cells also play a role in the immunological control of Leishmania major-induced lesions.

A murine monoclonal antibody (mAb) specific for apocytochrome c was found to be able to either inhibit or enhance the helper activity of mouse apocytochrome c-specific T cell clones and populations in a hapten (trinitrophenyl)-carrier (apocytochrome c) system of T-B cell cooperation. This effect of the mAb was carrier specific, could not be ascribed simply to a shift in the kinetics of the antibody response and was observed using apocytochrome c T helper cells of different mouse haplotypes. In addition, the anti-apocytochrome c mAb was able to inhibit specific T helper cell activity even when the T cells were triggered with antigen-presenting cells pulsed with antigen. Taken together, these results suggested that the mAb was inhibiting helper activity due to its ability to modify the interaction between T cells and antigen-presenting cells.