Interaction between CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, and its ligand CD40L, a 39-kDa glycoprotein, is essential for the development of humoral and cellular immune responses 1,2 . Selective blockade or activation of this pathway provides the ground for the development of new treatments against immunologically based diseases 3,4 and malignancies 5,6 . Like other members of the TNF superfamily, CD40L monomers self-assemble around a threefold symmetry axis to form noncovalent homotrimers that can each bind three receptor molecules 7,8 . Here, we report on the structure-based design of small synthetic molecules with C 3 symmetry that can mimic CD40L homotrimers. These molecules interact with CD40, compete with the binding of CD40L to CD40, and reproduce, to a certain extent, the functional properties of the much larger homotrimeric soluble CD40L. Architectures based on rigid C 3 -symmetric cores may thus represent a general approach to mimicking homotrimers of the TNF superfamily.CD40L is expressed mainly on activated T cells, whereas its cognate receptor, CD40, is constitutively expressed on dendritic cells (DC), macrophages and B cells. The engagement of CD40 by its ligand contributes to regulation of B cell proliferation, immunoglobulin production, immunoglobulin class switching, germinal center formation and development of B cell memory 1 . Moreover, CD40-CD40L interaction has an essential role in cellular immune response in which CD40 ligation activates DCs, 'licensing' them to present antigen to cytotoxic T cells by increasing MHC and costimulatory molecule expression and by producing high levels of IL-12, a T cell-stimulating cytokine [9][10][11] . Antibodies against CD40 with agonist activity have been used to increase immune response in infectious diseases 12,13 and in cancer immunotherapy 5,6 . All of these results underscore the important therapeutic applications that could emerge from the development of small-molecule CD40 agonists.Although ligand-induced dimerization is a general mechanism for activating receptors of cytokines and growth factors 14 , signaling through receptors of the TNFR superfamily strongly relies on the formation of stoichiometrically defined C 3 -symmetric complexes 7 . The structures of several TNF family members in complex with their cognate receptors show that each ligand homotrimer interacts with three monomeric receptor chains 7,15,16 . The geometry of the resulting 3:3 hexameric complex is favorable to the formation of an internal 3:3 signaling complex between the intracellular tail of the receptor and transduction proteins, ultimately activating downstream effector pathways 7 .Despite the difficulty in identifying small molecules that can disrupt protein-protein interactions, synthetic agonists of homodimeric cytokine receptors have been reported 17,18 . The ability of these molecules to dimerize cell-surface receptors is a major determinant of their effector functions 19 . In the present study, we have developed CD40L mimetics by integr...
SUMMARY:Trypanosoma cruzi, the etiologic agent of Chagas disease, induces infection that affects most immunocompetent cells. However, its effect on dendritic cells (DC) is still unknown in vivo. In this report, we show, by immunohistochemical staining, that T. cruzi infection triggers a huge increase in the number of CD11c ϩ DC in the spleen of infected mice at Days 14 and 21 post-inoculation (pi). In mice reaching the chronic phase (starting on Day 35 pi), the number of splenic DC (sDC) returned progressively to normal (ending on Day 98 pi). In the spleens of noninfected mice, most of the CD8␣ ϩ CD11c ϩ and CD8␣ Ϫ CD11c ϩ DC were found in the red pulp and the marginal and T-cell zones. However, starting on Day 14 pi, a progressive decline of CD8␣ ϩ CD11c ϩ was observed. In addition, sDC expressed low levels of the costimulatory molecule B7.2 at Days 14 and 21 pi, suggesting that they remained immature in the course of the infection. As expected, in lipopolysaccharide-treated and noninfected mice, the expression of B7.2 molecules was sharply up-regulated on sDC that migrated toward the T-cell zone. In contrast, upon lipopolysaccharide stimulation, sDC from T. cruzi-infected mice did not migrate toward the T-cell zone nor did they undergo maturation. Finally, white pulp was severely depleted in both CD4 ϩ and CD8 ϩ T cells at the peak of infection. Taken together, these results indicate that profound alterations of migration and maturation of sDC and depletion/redistribution of T cells occur during the acute phase of T. cruzi infection and could be part of another strategy to escape immune surveillance and to persist in the host. (Lab Invest 2003, 83:1373-1382. D evelopment of a specific and protective immune response against pathogens first depends on their interactions with dendritic cells (DC), which act as roving sentinels of the immune system. DC are found in most tissues and organs and constitute a complex system of professional APC (Mellman and Steinman, 2001). Immature DC capture pathogens or pathogenderived antigens. Then, upon activation by microbial components and/or cytokines, DC migrate to lymph nodes draining the site of invasion and spleen. During their migration, they undergo a process of maturation, losing their capacity to capture and process antigens but increasing their expression of MHC class II, costimulatory (CD40, CD80, CD86), and adhesion molecules (CD54) (Steinman et al, 1997). Finally, they differentiate into fully potent APC and they prime rare naïve T cells expressing the relevant T cell receptors and induce their differentiation and proliferation (Lanzavecchia and Sallusto, 2000).Trypanosoma cruzi is a hemoflagellate parasitic protozoa. It infects humans and domestic and wild mammals and is the etiologic agent of Chagas disease (Tarleton and Zhang, 1999). Experimental infection of BALB/c mice mimics the human disease. It displays an acute phase with parasitemia and mortality followed by a chronic phase during which parasites become undetectable in peripheral blood while persisting in...
Host resistance to Trypanosoma cruzi infection depends on a type 1 response characterized by a strong production of IL-12 and IFN-γ. Amplifying this response through CD40 triggering results in control of parasitemia. Two newly synthesized molecules (<3 kDa) mimicking trimeric CD40L (mini CD40Ls-1 and -2) bind to CD40, activate murine dendritic cells, and elicit IL-12 production. Wild-type but not CD40 knockout mice exhibited a sharp decrease of parasitemia and mortality when inoculated with T. cruzi mixed with miniCD40Ls. Moreover, the immunosuppression induced by T. cruzi infection was impaired in mice treated with miniCD40Ls, as shown by proliferation of splenic lymphocytes, percentage of CD8+ T cells, and IFN-γ production. Mice surviving T. cruzi infection in the presence of miniCD40L-1 were immunized against a challenge infection. Our results indicate that CD40L mimetics are effective in vivo and promote the control of T. cruzi infection by overcoming the immunosuppression usually induced by the parasites.
We have previously shown that infection by
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