Macrophage‐T cell interaction in experimental visceral leishmaniasis: failure to express costimulatory molecules on Leishmania‐infected macrophages and its implication in the suppression of cell‐mediated immunity

Abstract

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.

Macrophage Heterogeneity, Antigen Presentation, and Membrane Fluidity: Implications in Visceral Leishmaniasis

“…9H 3.5 and 7B7.3 (I-A d restricted T-cell hybridoma) specific for lambda repressor N-terminal sequence 12-26 [LEDARRLKAIYEKKK, defined as lR (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)], T-cell hybridomas and peptides were kind gifts of Professor M.L. Gefter, Massachusetts Institute of Technology, Cambridge, MA, USA.…”

“…The lR(12-26) is I-A d restricted, whereas the lambda repressor sequence 80±94 [IAREIYEMYEAVSMQ, defined as lR (80±94)] is I-A k restricted [18]. Both the lR (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) and the lR(80±94) peptides show characteristics of amphipathic alpha helix and possess motif proposed by Rothbred [18].…”

“…After extensive washing when the radioactivity detected in the washing medium was less than 200 cpm, the total radioactivity of the pellet was measured. Competitive inhibition of binding of labelled peptide by unlabelled peptide was done on whole cell as described [29,30] to show the specificity of 125 IlIR (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) binding. Here the fixed Mfs were pulsed for 6 h with either unlabelled lR (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) or unlabelled unrelated peptide sequence lR(80±94) at a concentration of 5 mm and the extent of cell associated radioactivity was measured as described [31].…”

“…It was observed that 6 I-LM had no inhibitory effect on other Mf population and in fact an additive effect on antigen presentation was observed when 6 I-LM was mixed with either 6 I-SM or 6 N-SM. an unrelated sequence, lR(80±94), followed by incubation with 125 llR (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). It was observed that pulsing with unlabelled lR(12-26) inhibited the binding of 125 llR (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) to the extent of 35% (Fig.…”

Mechanisms of Immune Evasion in Leishmaniasis

“…In Leishmania -infected macrophages, there is a reduced expression of B7-1 even after lipopolysaccharide (LPS) stimulation, possibly mediated by parasite-induced prostaglandins (Saha, Das, Vohra, Ganguly, & Mishra, 1995). Similarly, during L. major infection B7-1 expression is down-regulated in epidermal cells from susceptible mice (Mbow, DeKrey, & Titus, 2001).…”