Class II MHC/peptide interaction in Leishmania donovani infection: implications in vaccine design.

We show that Leishmania donovani-infected macrophages (MΦs) are capable of stimulating MHC class II (MHC-II)-restricted T cells at 6 h of infection. At 48 h, infected MΦs (I-MΦs) failed to stimulate MHC-II-restricted T cells but not MHC class I-restricted ones, in contrast to normal MΦs. Such I-MΦs could stimulate T cells at a higher Ag concentration, indicating that general Ag processing and trafficking of peptide-MHC-II complexes are not defective. Analysis of the kinetic parameters, like "kon" and "koff," showed that peptide-MHC-II complex formation is compromised in I-MΦs compared with normal MΦs. This indicates interference in loading of the cognate peptide to MHC-II, which may be due to the presence of a noncognate molecule. This notion received support from the finding that exposure of I-MΦs to low pH or treatment with 2-(1-adamantyl)-ethanol, a molecule that favors peptide exchange, led to T cell activation. When treated with 2-(1-adamantyl)-ethanol, splenocytes from 8 wk-infected BALB/c mice showed significantly higher antileishmanial T cell expansion in vitro compared with untreated controls. Hence, it is tempting to speculate that high, but not low, concentrations of cognate peptide may favor peptide exchange in I-MΦs, leading to expansion of the antileishmanial T cell repertoire. The results suggest that a high Ag dose may overcome compromised T cell responses in visceral leishmaniasis, and this has an important implication in therapeutic vaccine design.