Nitric oxide inhibits the accumulation of CD4+CD44hiTbet+CD69lo T cells in mycobacterial infection.
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(+)CD44(hi) 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 CD69(hi) and CD69(lo) populations, with the CD69(lo) population only able to accumulate during chronic infection within infected nos2(-/-) mice. Transcriptomic comparison between CD4(+)CD44(hi)CD69(hi) and CD4(+)CD44(hi)CD69(lo) populations revealed that CD4(+)CD44(hi)CD69(lo) cells had higher expression of the integrin itgb1/itga4 (VLA-4, CD49d/CD29). Inhibition of Nos2 activity allowed increased accumulation of the CD4(+) CD44(hi)T-bet(+)CD69(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.
Trudeau Institute Inc, Saranac Lake, NY 12983, USA.
John E
JE
Pearl
Egidio
E
Torrado
Michael
M
Tighe
Jeffrey J
JJ
Fountain
Alejandra
A
Solache
Tara
T
Strutt
Susan
S
Swain
Rui
R
Appelberg
Andrea M
AM
Cooper
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology; D015769:Granuloma, Respiratory Tract / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000662:veterinary; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009162:Mycobacterium avium / Q000276:immunology*; D009569:Nitric Oxide / Q000235:genetics / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000662:veterinary; D000098815:T-bet Transcription Factor; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D000099192:CD69 Antigens; C496317:Nos2 protein, mouse