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J Infect Dis. 2018 Oct 11. doi: 10.1093/infdis/jiy586. [Epub ahead of print]

Inhibiting Adenosine Receptor Signaling Promotes Accumulation of Effector CD4+ T Cells in the Lung Parenchyma During Severe Tuberculosis.

Author information

1
Department of Immunology, Biomedical Science Institute, University of São Paulo (USP), São Paulo, Brazil.
2
Laboratory of Biology of Recognition, State University of North Fluminense, Campos dos Goytacazes, Brazil.
3
Department of Clinical Chemistry and Toxicology, Faculty of Pharmaceutical Sciences, USP, São Paulo, Brazil.

Abstract

Background:

Tuberculous pneumonia, necrotic granulomatous lesions, and bacterial dissemination characterize severe forms of mycobacterial infection.

Methods:

To evaluate the pulmonary CD4+ T-cell response during severe tuberculosis, C57BL/6 mice were infected with approximately 100 bacilli of 3 hypervirulent mycobacterial isolates (Mycobacterium tuberculosis strain Beijing 1471 and Mycobacterium bovis strains B2 and MP287/03) or the H37Rv M tuberculosis strain as reference for mycobacterial virulence. Because high expression of both CD39 and CD73 ectonucleotidases was detected on parenchymal CD4+ T cells, we investigated whether CD4+ T-cell suppression in the context of severe disease was due to the extracellular adenosine accumulation that resulted from tissue damage.

Results:

Lowest expression of CD69, which is an activation marker implicated in maintaining cells in tissues, was observed in lungs from mice displaying the most severe pulmonary pathology. Reduced interferon (IFN)γ-producing CD4+ T cells were also found in the lung of these mice. Intranasal administration of the adenosine receptor antagonist caffeine substantially enhanced the frequency and number of parenchymal CD4+ T cells as well as both CD69 expression and IFNγ production.

Conclusions:

These results indicate that adenosine, which may be generated by extracellular adenosine triphosphate degradation, impairs the parenchymal CD4+ T-cell response and contributes to the development of severe tuberculosis.

PMID:
30307561
DOI:
10.1093/infdis/jiy586

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