title: T cells from Leishmania major-susceptible BALB/c mice have a defect in efficiently up-regulating CXCR3 upon activation.
abstract: 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.
authors.affiliation: Department of Microbiology, The Ohio State University, Columbus, OH 43221, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Barbi
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
mesh_terms: 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*
chemical_list: C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3
references.citation: Infect Immun. 2000 Apr;68(4):1773-80
references.pmid: 10722563
references.citation: J Immunol. 2000 Aug 1;165(3):1395-402
references.pmid: 10903743
references.citation: J Immunol. 2000 Aug 1;165(3):1548-56
references.pmid: 10903763
references.citation: Immunol Lett. 2000 Dec 1;75(1):41-4
references.pmid: 11163865
references.citation: J Immunol. 2001 Feb 15;166(4):2793-800
references.pmid: 11160346
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15137-42
references.pmid: 11752460
references.citation: J Exp Med. 2002 May 20;195(10):1257-66
references.pmid: 12021306
references.citation: Eur J Immunol. 2002 Jun;32(6):1792-801
references.pmid: 12115663
references.citation: Am J Transplant. 2003 Dec;3(12):1538-49
references.pmid: 14629284
references.citation: Immunobiology. 1989 Oct;179(4-5):412-21
references.pmid: 2575598
references.citation: Eur J Immunol. 1990 Sep;20(9):2067-74
references.pmid: 1976523
references.citation: J Immunol. 1991 Nov 1;147(9):3149-55
references.pmid: 1833466
references.citation: Annu Rev Immunol. 1995;13:151-77
references.pmid: 7612219
references.citation: J Exp Med. 1998 Jan 5;187(1):129-34
references.pmid: 9419219
references.citation: Int Immunol. 1998 Dec;10(12):1853-61
references.pmid: 9885906
references.citation: Eur J Immunol. 2005 Feb;35(2):515-23
references.pmid: 15668916
references.citation: J Neuroimmunol. 2005 May;162(1-2):71-80
references.pmid: 15833361
references.citation: Lancet. 2005 Oct 29-Nov 4;366(9496):1561-77
references.pmid: 16257344
references.citation: Blood. 2005 Nov 15;106(10):3432-9
references.pmid: 16014561
references.citation: J Immunol. 2006 Nov 1;177(9):5890-901
references.pmid: 17056513
references.citation: J Exp Med. 2007 Feb 19;204(2):285-97
references.pmid: 17283207
references.citation: J Infect Dis. 2007 Jun 1;195(11):1713-7
references.pmid: 17471442
references.citation: Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2561-9
references.pmid: 17525185
references.citation: J Immunol. 2007 Jun 15;178(12):8028-35
references.pmid: 17548640
references.citation: Blood. 2007 Sep 15;110(6):2215-6
references.pmid: 17785588
references.citation: Eur J Immunol. 2008 Apr;38(4):1082-95
references.pmid: 18383042