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

Naoko Sato, William A. Kuziel, Peter Melby, Robert Lee Reddick, Vannessa Kostecki, Weiguo Zhao, Nobuyo Maeda, Sunil K. Ahuja, Seema S. Ahuja

Research output: Contribution to journalArticle

138 Citations (Scopus)

Abstract

We investigated the immune responses in mice lacking CCR2, CCRS, or macrophage inflammatory protein-1α (MIP-1α), a ligand for CCRS, in two situations: following T cell stimulation or after challenge with Leishmania donovani, an intracellular microbe whose control is dependent on a Th1 immune response. Mice deficient in CCRS, MIP-1α, or CCR2 had reduced IFN- γ/responses following ligation of the TCR. Reduced IFN-γ/responses following PMA and ionomycin were also observed in CD8+ T cells of CCR5(-/-) and CCR2(-/-) mice. During the early phases of infection, all three knockout mice had low Ag-specific IFN-γ/responses. However, this reduced IFN- γ/response was overcome during a state of persistent Ag stimulation (chronic 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-γ response was evident in CCR5(-/-) and MIP-1α(-/-) mice, and this correlated with an enhanced control of parasite replication. Although granuloma formation was abnormal in each of the knockout mice, there was no correlation between the number or architecture of the granulomas and parasite burden. Collectively, these findings indicate an important role for CCRS, MIP-1α, and CCR2 in granulomatous inflammation, and that CCR5 and MIP-1α, possibly acting through CCR5, might play a deleterious role in the outcome of chronic L. donovani infection. Our data also suggest that there might be cross-talk between TCR and chemokine receptor signaling pathways.

Original languageEnglish (US)
Pages (from-to)5519-5525
Number of pages7
JournalJournal of Immunology
Volume163
Issue number10
StatePublished - Nov 15 1999
Externally publishedYes

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CCR5 Receptors
Macrophage Inflammatory Proteins
Leishmania donovani
Infection Control
Infection
Granuloma
Knockout Mice
Communicable Disease Control
T-Lymphocytes
Ionomycin
Chemokine Receptors
Ligation
Parasites
Ligands
Inflammation
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

Defects in the generation of IFN-γ/are overcome to control infection with Leishmania donovani in CC chemokine receptor (CCR) 5-, macrophage inflammatory protein-1α-, or CCR2-deficient mice. / Sato, Naoko; Kuziel, William A.; Melby, Peter; Reddick, Robert Lee; Kostecki, Vannessa; Zhao, Weiguo; Maeda, Nobuyo; Ahuja, Sunil K.; Ahuja, Seema S.

In: Journal of Immunology, Vol. 163, No. 10, 15.11.1999, p. 5519-5525.

Research output: Contribution to journalArticle

Sato, Naoko ; Kuziel, William A. ; Melby, Peter ; Reddick, Robert Lee ; Kostecki, Vannessa ; Zhao, Weiguo ; Maeda, Nobuyo ; Ahuja, Sunil K. ; Ahuja, Seema S. / Defects in the generation of IFN-γ/are overcome to control infection with Leishmania donovani in CC chemokine receptor (CCR) 5-, macrophage inflammatory protein-1α-, or CCR2-deficient mice. In: Journal of Immunology. 1999 ; Vol. 163, No. 10. pp. 5519-5525.
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abstract = "We investigated the immune responses in mice lacking CCR2, CCRS, or macrophage inflammatory protein-1α (MIP-1α), a ligand for CCRS, in two situations: following T cell stimulation or after challenge with Leishmania donovani, an intracellular microbe whose control is dependent on a Th1 immune response. Mice deficient in CCRS, MIP-1α, or CCR2 had reduced IFN- γ/responses following ligation of the TCR. Reduced IFN-γ/responses following PMA and ionomycin were also observed in CD8+ T cells of CCR5(-/-) and CCR2(-/-) mice. During the early phases of infection, all three knockout mice had low Ag-specific IFN-γ/responses. However, this reduced IFN- γ/response was overcome during a state of persistent Ag stimulation (chronic 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-γ response was evident in CCR5(-/-) and MIP-1α(-/-) mice, and this correlated with an enhanced control of parasite replication. Although granuloma formation was abnormal in each of the knockout mice, there was no correlation between the number or architecture of the granulomas and parasite burden. Collectively, these findings indicate an important role for CCRS, MIP-1α, and CCR2 in granulomatous inflammation, and that CCR5 and MIP-1α, possibly acting through CCR5, might play a deleterious role in the outcome of chronic L. donovani infection. Our data also suggest that there might be cross-talk between TCR and chemokine receptor signaling pathways.",
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AU - Sato, Naoko

AU - Kuziel, William A.

AU - Melby, Peter

AU - Reddick, Robert Lee

AU - Kostecki, Vannessa

AU - Zhao, Weiguo

AU - Maeda, Nobuyo

AU - Ahuja, Sunil K.

AU - Ahuja, Seema S.

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