Defects in the generation of IFN-gamma are overcome to control infection with Leishmania donovani in CC chemokine receptor (CCR) 5-, macrophage inflammatory protein-1 alpha-, or CCR2-deficient mice

We investigated the immune responses in mice lacking CCR2, CCR5, or macroph age inflammatory protein-la (MIP-1 alpha), a ligand for CCR5, in two situat ions: following T cell stimulation or after challenge with Leishmania donov ani, an intracellular microbe whose control is dependent on a Th1 immune re sponse. Mice deficient in CCR5, MIP-1 alpha, or CCR2 had reduced IFN-gamma responses following ligation of the TCR, Reduced IFN-gamma responses follow ing PMA and ionomycin were also observed in CD8(+) T cells of CCR5(-/-) and CCR2(-/-) mice. During the early phases of infection, all three knockout m ice had low Ag-specific IFN-gamma responses. However, this reduced IFN-gamm a response was overcome during a state of persistent Ag stimulation (chroni c infection), and was not associated with an adverse parasitologic outcome in any of the gene-targeted mouse strains, To the contrary, during the late phase of infection, an exaggerated Ag-specific IFN-gamma response was evid ent in CCR5(-/-) and MIP-1 alpha(-/-) mice, and this correlated,vith an enh anced control of parasite replication. Although granuloma formation was abn ormal in each of the knockout mice, there was no correlation between the nu mber or architecture of the granulomas and parasite burden. Collectively, t hese findings indicate an important role for CCR5, MIP-1 alpha, and CCR2 in granulomatous inflammation, and that CCR5 and MIP-1 alpha, possibly acting through CCR5, might play a deleterious role in the outcome of chronic L, d onovani infection, Our data also suggest that there might be cross-talk bet ween TCR and chemokine receptor signaling pathways.