Role of costimulatory molecules in immune response of patients with cutaneous leishmaniasis

Abstract

T cell-mediated immunity is critical in resistance against Leishmania parasites, and T cell activation requires signals provided by costimulatory molecules. Herein we evaluated the role of costimulatory molecules on cytokine production and T cell surface molecule expression by peripheral blood mononuclear cells (PBMC) from cutaneous leishmaniasis (CL) patients. PBMC from CL patients were stimulated with soluble Leishmania antigen (SLA, 10 microg/ml), in the presence or absence of soluble CTLA4-Ig to block CD28-B7 interaction or in the presence or absence of anti-human CD40L to block CD40-CD40L interaction. Supernatants were harvested to evaluate tumor necrosis factor alpha (TNF-alpha), interleukin 10 (IL-10), transforming growth factor beta (TGF-beta) and interferon gamma (IFN-gamma) production by ELISA. Cells were harvested after 48 h of culture, stained for specific activation markers and analyzed by flow cytometry. Results show that the blockade of CD28-B7 interaction by CTLA4-Ig downmodulated IFN-gamma, IL-10, and TNF-alpha secretion by PBMC from CL patients. No alteration was detected on either TGF-beta production or the expression of CTLA44 or CD25 on CD4+ and CD8+ T cells. When the CD40-CD40L interaction was blockade using anti-CD40L, we did not observe changes in cytokine production or in surface molecule expression. The blockade of the CD28-B7 interactions by CTLA4-Ig also did not alter cytokine production in volunteers immunized against tetanus toxoid (TT). Taken together, these data suggest that the interaction of CTLA4 and CD28-B7 is a TGF-beta-independent mechanism that specifically downmodulates the immune response in cutaneous leishmaniasis patients.

Influence of CTLA-4 gene polymorphism in autoimmune and infectious diseases

“…These cytokines are essential to control parasite multiplication because they influence macrophage activation, and the blockade of the CD28:B7 pathway leads to downmodulation of both proinflamatory cytokines. The three active forms of American tegumentary L are characterized by cytokine patterns in lesions: LCL by a Th1 response, DCL by a Th2 response, and ICL by a mixed pattern of cytokines [31]. CTLA-4 engagement during differentiation inhibits polarization of naive CD4 ϩ cells to the Th2 but not the Th1 cell subset.…”

Differential Regulation of the Immune Response in the Spleen and Liver of Mice Infected withLeishmania donovani

“…The fact that CD8 T-cell functions are not completely restored by B7-H1 blockade suggests the involvement of additional pathways in the suppression of cytokine production by these cells. Other inhibitory molecules, such as LAG3 [18–20] and CTLA4 [21, 22], may also be involved in this suppression. Nevertheless, the partial recovery of CD8 T cell functions is sufficient to reduce the splenic parasite burden, suggesting that B7-H1 blockade and the reactivation of CD8 T-cells may be exploited as a therapeutic intervention.…”

The Role of Negative Costimulators During Parasitic Infections

“…When PBMCs from patients with cutaneous leishmaniasis (CL) were stimulated with soluble Leishmania antigen in the presence of CTLA-4Ig which leads to a blockade of the costimulatory CD28/B7 interaction, a downmodulation of IFN-, IL-10 and TNF-secretion but no alteration in TGF-production was detected [33].…”

“…On the one hand, BTLA TGF--independent immune suppression in human visceral leishmaniasis by CTLA-4 engagement [33] Leishmania ssp.…”