T cells from Leishmania major-susceptible BALB/c mice have a defect in efficiently up-regulating CXCR3 upon activation.
Genetic background influences the outcome of Leishmania major infection. C57BL/6 mice mount a Th1 response and resolve infection. In contrast, BALB/c mice mount a Th2 response and develop chronic lesions. This susceptible phenotype is seen even though BALB/c mice generate IFN-gamma-producing T cells at proportions similar to C57BL/6 mice in their lymph nodes (LN) early after infection. We had previously shown that chemokine receptor CXCR3 mediates immunity against L. major by recruiting IFN-gamma-producing T cells to the lesions of C57BL/6 mice. Therefore, we hypothesized that IFN-gamma-secreting T cells in BALB/c mice are unable to confer protection because they may be defective in up-regulating CXCR3. To test this hypothesis, we analyzed kinetics of CXCR3-expressing T cells in the LN and lesions of BALB/c and C57BL/6 mice during L. major infection. Additionally, we compared the ability of T cells from BALB/c and C57BL/6 mice to up-regulate CXCR3 upon activation. We found that resolution of L. major infection in C57BL/6 mice was associated with an increase in the proportion of CXCR3(+) T cells in regional LN and lesions, whereas disease progression in BALB/c mice was associated with a decrease in these populations. Anti-CD3/CD28-activated T cells from naive BALB/c but not C57BL/6 mice were defective in up-regulating CXCR3. Impaired induction of CXCR3 on BALB/c T cells was not due to lack of IFN-gamma and was mediated partially by IL-10 but not IL-4 or IL-13. We propose that defective CXCR3 up-regulation on T cells in BALB/c mice may contribute to L. major susceptibility.
Barbi
Joseph
J
Department of Microbiology, The Ohio State University, Columbus, OH 43221, USA.
Brombacher
Frank
F
Satoskar
Abhay R
AR
D000818:Animals; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054367:Receptors, CXCR3 / Q000096:biosynthesis / Q000172:deficiency* / Q000502:physiology; D013045:Species Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000469:parasitology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3
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