Transgenic Expression of CXCR3 on T Cells Enhances Susceptibility to Cutaneous Leishmania major Infection by Inhibiting Monocyte Maturation and Promoting a Th2 Response
| Autor: | Cesar Terrazas, Abhay R. Satoskar, Chad A. Rappleye, Ran Dong, Steve Oghumu, Ariel Holovatyk, James C. Stock, Sanjay Varikuti, Arlene H. Sharpe, Jessica A. Edwards |
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| Rok vydání: | 2015 |
| Předmět: |
Genetically modified mouse
Receptors CXCR3 Transgene Immunology Gene Expression Leishmaniasis Cutaneous Mice Transgenic CXCR3 Microbiology Monocytes Parasite Load Th2 Cells Cutaneous leishmaniasis medicine Animals Leishmania major Lymph node Skin Mice Inbred BALB C biology Intracellular parasite medicine.disease biology.organism_classification Molecular biology Mice Inbred C57BL Disease Models Animal Infectious Diseases medicine.anatomical_structure Female Parasitology Disease Susceptibility Lymph Fungal and Parasitic Infections |
| Zdroj: | Infection and Immunity. 83:67-76 |
| ISSN: | 1098-5522 0019-9567 |
| DOI: | 10.1128/iai.02540-14 |
| Popis: | 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 . |
| Databáze: | OpenAIRE |
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