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T Cells from Leishmania major-Susceptible BALB/c Mice Have a Defect in Efficiently Up-Regulating CXCR3 upon Activation¹

Joseph Barbi^*, Frank Brombacher and Abhay R. Satoskar^2,*

^* Department of Microbiology, The Ohio State University, Columbus, OH 43221; and Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Health Sciences Faculty, University of Cape Town, Wernher Beit South, Cape Town, South Africa

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--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--producing T cells to the lesions of C57BL/6 mice. Therefore, we hypothesized that IFN--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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant R01 AI A151823 (to A.R.S.).

² Address correspondence and reprint requests to Dr. Abhay R. Satoskar, Department of Microbiology, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43221. E-mail address: satoskar.2{at}osu.edu

³ Abbreviations used in this paper: LN, lymph node; dLN, draining LN; WT, wild type.