期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 42, 期 12, 页码 3267-3279出版社
WILEY
DOI: 10.1002/eji.201142158
关键词
Bacterial infection; CD4+T cells; Cell differentiation; Immunopathology; Inflammation
类别
资金
- Trudeau Institute, Inc.
- NIH [AI46530, AI069121]
- American Lung Association DeSouza Award
- FCT (Fundacao para a Ciencia e a Tecnologia) [PTDC/SAU-MII/099102/2008]
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-MII/099102/2008] Funding Source: FCT
Animals lacking the inducible nitric oxide synthase gene (nos2-/-) are less susceptible to Mycobacterium avium strain 25291 and lack nitric oxide-mediated immunomodulation of CD4+ T cells. Here we show that the absence of nos2 results in increased accumulation of neutrophils and both CD4+ and CD8+ T cells within the M. avium containing granuloma. Examination of the T-cell phenotype in M. avium infected mice demonstrated that CD4+CD44hi effector T cells expressing the Th1 transcriptional regulator T-bet (T-bet+) were specifically reduced by the presence of nitric oxide. Importantly, the T-bet+ effector population could be separated into CD69hi and CD69lo populations, with the CD69lo population only able to accumulate during chronic infection within infected nos2-/- mice. Transcriptomic comparison between CD4+CD44hiCD69hi and CD4+CD44hiCD69lo populations revealed that CD4+CD44hiCD69lo cells had higher expression of the integrin itgb1/itga4 (VLA-4, CD49d/CD29). Inhibition of Nos2 activity allowed increased accumulation of the CD4+CD44hiT-bet+CD69lo population in WT mice as well as increased expression of VLA-4. These data support the hypothesis that effector T cells in mycobacterial granulomata are not a uniform effector population but exist in distinct subsets with differential susceptibility to the regulatory effects of nitric oxide.
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