title: Transgenic expression of CXCR3 on T cells enhances susceptibility to cutaneous Leishmania major infection by inhibiting monocyte maturation and promoting a Th2 response.
abstract: Cutaneous leishmaniasis, caused mainly by Leishmania major, an obligate intracellular parasite, is a disfiguring disease characterized by large skin lesions and is transmitted by a sand fly vector. We previously showed that the chemokine receptor CXCR3 plays a critical role in mediating resistance to cutaneous leishmaniasis caused by Leishmania major. Furthermore, T cells from L. major-susceptible BALB/c but not L. major-resistant C57BL/6 mice fail to efficiently upregulate CXCR3 upon activation. We therefore examined whether transgenic expression of CXCR3 on T cells would enhance resistance to L. major infection in susceptible BALB/c mice. We generated BALB/c and C57BL/6 transgenic mice, which constitutively overexpressed CXCR3 under a CD2 promoter, and then examined the outcomes with L. major infection. Contrary to our hypothesis, transgenic expression of CXCR3 (CXCR3(Tg)) on T cells of BALB/c mice resulted in increased lesion sizes and parasite burdens compared to wild-type (WT) littermates after L. major infection. Restimulated lymph node cells from L. major-infected BALB/c-CXCR3(Tg) mice produced more interleukin-4 (IL-4) and IL-10 and less gamma interferon (IFN-γ). Cells in draining lymph nodes from BALB/c-CXCR3(Tg) mice showed enhanced Th2 and reduced Th1 cell accumulation associated with increased neutrophils and inflammatory monocytes. However, monocytes displayed an immature phenotype which correlated with increased parasite burdens. Interestingly, transgenic expression of CXCR3 on T cells did not impact the outcome of L. major infection in C57BL/6 mice, which mounted a predominantly Th1 response and spontaneously resolved their infection similar to WT littermates. Our findings demonstrate that transgenic expression of CXCR3 on T cells increases susceptibility of BALB/c mice to L. major.
authors.affiliation: Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, USA Department of Oral Biology, Ohio State University College of Dentistry, Columbus, Ohio, USA oghumu.1@osu.edu abhay.satoskar@osumc.edu.
authors.forename: Steve
authors.initials: S
authors.lastname: Oghumu
authors.affiliation: Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Stock
authors.affiliation: Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Varikuti
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Dong
authors.affiliation: Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: Cesar
authors.initials: C
authors.lastname: Terrazas
authors.affiliation: Department of Microbiology, Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Edwards
authors.affiliation: Department of Microbiology, Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Rappleye
authors.affiliation: Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Holovatyk
authors.affiliation: Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Arlene
authors.initials: A
authors.lastname: Sharpe
authors.affiliation: Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, USA Department of Microbiology, Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA oghumu.1@osu.edu abhay.satoskar@osumc.edu.
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D015870:Gene Expression; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology*; D059208:Parasite Load; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000469:parasitology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3