Nitric oxide inhibits the accumulation of CD 4 + CD 44 hi T bet + CD 69 lo T cells in mycobacterial infection

• Published in: European journal of immunology 2012-12, Vol.42 (12), p.3267-3279
• Main Authors: Pearl, John E., Torrado, Egidio, Tighe, Michael, Fountain, Jeffrey J., Solache, Alejandra, Strutt, Tara, Swain, Susan, Appelberg, Rui, Cooper, Andrea M.
• Format: Article
• Language: English
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201142158

Animals lacking the inducible nitric oxide synthase gene ( nos2 −/− ) are less susceptible to Mycobacterium avium strain 25291 and lack nitric oxide‐mediated immunomodulation of CD 4 + T cells. Here we show that the absence of nos2 results in increased accumulation of neutrophils and both CD 4 + and CD 8 + T cells within the M . avium containing granuloma. Examination of the T ‐cell phenotype in M . avium infected mice demonstrated that CD 4 + CD 44 hi effector T cells expressing the T h1 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 CD 69 hi and CD 69 lo populations, with the CD 69 lo population only able to accumulate during chronic infection within infected nos2 −/− mice. Transcriptomic comparison between CD 4 + CD 44 hi CD 69 hi and CD 4 + CD 44 hi CD 69 lo populations revealed that CD 4 + CD 44 hi CD 69 lo cells had higher expression of the integrin itgb1/itga4 ( VLA ‐4, CD 49d/ CD 29). Inhibition of N os2 activity allowed increased accumulation of the CD 4 + CD 44 hi T ‐bet + CD 69 lo 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.