期刊
JOURNAL OF LEUKOCYTE BIOLOGY
卷 91, 期 2, 页码 311-320出版社
WILEY
DOI: 10.1189/jlb.0711364
关键词
alpha 5 beta 1 integrin; FAK; Pyk2; fibronectin; RGD motif
资金
- NIH [AI027243, HL055967, HHSN266200700022C/NO1-AI-70022, AI069085, AI034343, AI035726]
- American Lung Association [RG48786N]
- Case Western Reserve University/University Hospital Center for AIDS Research [P30 AI036219]
- Case Comprehensive Cancer Center Cytometry Core Facility
- Veterans Hospital of Cleveland
Mtb regulates many aspects of the host immune response, including CD4(+) T lymphocyte responses that are essential for protective immunity to Mtb, and Mtb effects on the immune system are paradoxical, having the capacity to inhibit (immune evasion) and to activate (adjuvant effect) immune cells. Mtb regulates CD4(+) T cells indirectly (e.g., by manipulation of APC function) and directly, via integrins and TLRs expressed on T cells. We now report that previously uncharacterized Mtb protein Rv2468c/MT2543 can directly regulate human CD4(+) T cell activation by delivering costimulatory signals. When combined with TCR stimulation (e.g., anti-CD3), Rv2468c functioned as a direct costimulator for CD4(+) T cells, inducing IFN-gamma secretion and T cell proliferation. Studies with blocking antibodies and soluble RGD motifs demonstrated that Rv2468c engaged integrin VLA-5 (alpha 5 beta 1) on CD4(+) T cells through its FN-like RGD motif. Costimulation by Rv2468c induced phosphorylation of FAKs and Pyk2. These results reveal that by expressing molecules that mimic host protein motifs, Mtb can directly engage receptors on CD4(+) T cells and regulate their function. Rv2468c-induced costimulation of CD4(+) T cells could have implications for TB immune pathogenesis and Mtb adjuvant effect. J. Leukoc. Biol. 91: 311-320; 2012.
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