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Highly virulent strains of Trypanosoma cruzi are frequently used as murine models of Chagas’ disease. However, these strains do not fully represent the spectrum of parasites involved in the human infection. In this paper, we analysed parasitaemia, mortality, tissue pathology and parasite-specific IgG serum levels in immune-deficient mice infected with Sylvio X10/4 parasites, a T. cruzi derived from a chagasic patient that yields very low parasitaemias and in C3H/HePAS mice induces a chronic cardiopathy resembling the human disease. IFN- γ was identified as a crucial element for parasite control as its absence determined a drastic increase in parasitaemia, tissue parasitism, leukocyte infiltrates at the heart and striated muscles and mortality. The lack of IFN- γ or IL-12p40, a molecule shared by IL-12 and IL-23, also resulted in spinal cord lesions and a progressive paralysis syndrome. Whereas IgG2a was the main Ig isotype in infected C57BL/6 mice, IL-12p40-KO mice produced IgG2a and IgG1 and IFN- γ-KO mice produced only IgG1. The IFN- γ-protective effect was not essentially mediated by nitric oxide (NO), inasmuch as infected iNOS-KO mice showed no parasitaemia and low tissue damage. Mice deficient in CD4+ or CD8+ T cells showed an intermediate phenotype with increased mortality and tissue pathology but no parasitaemia. Interestingly, CD28-KO mice were unable to produce anti- T. cruzi IgG antibodies but presented moderate tissue pathology and managed to control the infection. Thus, differently from infections with high virulence parasites, neither IgG, NO nor CD28-mediated signalling are essential for the non-sterile control of Sylvio X10/4 parasites. [ABSTRACT FROM AUTHOR]

T lymphocytes are activated by the interaction between the T-cell antigen receptor (TCR) and peptides presented by major histocompatibility complex (MHC) molecules. The avidity of this TCR–pMHC interaction is very low. Therefore, several hypotheses have been put forward to explain how T cells become specifically activated despite this handicap: conformational change model, aggregation model, kinetic segregation model, sequential interaction model and permissive geometry model. In the present paper, we conducted experiments to distinguish between the TCR-aggregation model and the TCR-conformational change model. The results obtained using a TCR capture ELISA with Brij 98-solubilized TCR molecules from normal or activated T cells showed that the ligand–TCR interaction causes structural changes in the CD3ε cytoplasmic tail as well as in the extracellular TCRβ FG loop region. Size-fractionation experiments with Brij 98-solubilized TCR/CD3/co-receptor complexes from naïve or activated CD4+ or CD8+ T cells demonstrated that such complexes are found as either dimers or tetramers. No monomers or multimers were detected. We propose that: (1) ligand–TCR interaction results in conformational changes in the CD3ε cytoplasmic tail leading to T-cell activation; (2) CD3ε cytoplasmic tail interaction with intracellular proteins may dissociate pMHC and co-receptors (CD4 or CD8) from TCR/CD3 complexes, thus leading to the arrest of T-cell activation; and (3) T-cell activation appears to occur among dimers or tetramers of TCR/CD3/co-receptor complexes interacting with self and non-self (foreign) peptide-MHC complexes. [ABSTRACT FROM AUTHOR]

Development and evaluation of new vaccines and immunotherapy against tuberculosis demand a better understanding of the immune mechanisms in this disease. Costimulatory signals and intercellular contact seem to be pivotal in determining whether recognition of antigen by T cells leads to activation or anergy. In this paper, we show that virulent M. tuberculosis H37Rv downmodulates the ex vivo expression of CD18 and CD86 on peritoneal macrophages and VLA-4 on lymphocytes but does not disturb the in vitro production of interleukin (IL)-12 and interferon (IFN)-γ after intraperitoneal infection. In addition, splenocytes from infected mice produce IL-10, while the expression of cell surface receptors is unchanged. The interplay among IL-12, IFN-γ and IL-10 in vivo and the downmodulation of cell-surface receptors during the infection at the inflammatory site may contribute to the explanation of the maintenance of infection. [ABSTRACT FROM AUTHOR]