The most important immunopathological consequence of
infection with Leishmania seen in murine and human hosts is the suppression of T cell-mediated immune responses to both
mitogens and leishmanial
antigens. It has been suggested that this suppression is mediated by macrophages, either by defective antigen processing and presentation or by the elaboration of suppressive mediators like
prostaglandins. Optimum activation of T helper cells requires not only
T cell receptor occupancy by the
antigen-Ia complex, but also costimulatory signals provided by the antigen-presenting cells. We investigated the status of several costimulatory molecules on infected macrophages from both genetically susceptible BALB/c and resistant C57BL/6 mice. Our results demonstrate that upon parasitization, the macrophages become unable to deliver costimulatory signals to T helper cells, and that this effects is mediated by
prostaglandins, as the inhibition of its synthesis by
indomethacin recovered the defect. Upon
infection with L. donovani, B7-1 expression was decreased, while
ICAM-1 was marginally increased in BALB/c macrophages and there was no significant change in the expression of B7-1 and
ICAM-1 in Leishmania-infected C57BL/6 macrophages. Expression of
VCAM-1 did not change during
infection. This selective alteration in the expression of costimulatory molecules on L. donovani-infected BALB/c macrophages was caused by the living parasite, as shown by the fact that killing of the parasites by stibogluconate led to no alteration in the levels of costimulatory molecules. We found that the change in B7-1 expression on the surface of infected macrophages resulted in the inhibition of delayed-type
hypersensitivity-mediating functions of T helper cells from BALB/c mice. The results described in this study not only throw light on the possible mechanism of leishmanial pathogenesis, but also open up the possibility of
immunotherapy of
leishmaniasis by selective manipulation of costimulatory molecules.