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

Autor(es)

Amaral, Eduardo P. ^[1] ; de Salles, Erika Machado ^[1] ; Barbosa Bomfim, Caio Cesar ^[1] ; Salgado, Rafael Moyses ^[1] ; Almeida, Fabricio M. ^[2] ; de Souza, Paula Carolina ^[1] ; Alvarez, Jose Maria ^[1] ; Hirata, Mario H. ^[3] ; Lasunskaia, Elena B. ^[2] ; D'Imperio-Lima, Maria Regina ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil

^[2] State Univ North Fluminense, Lab Biol Recognit, Campos Dos Goytacazes - Brazil

^[3] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin Chem & Toxicol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Infectious Diseases; v. 219, n. 6, p. 964-974, MAR 15 2019.
• Citações Web of Science: 2

Resumo

The detection of extracellular adenosine triphosphate (eATP) by P2X7 receptor promotes the development of severe tuberculosis. This study shows that adenosine, a byproduct of eATP degradation, impairs the CD4+ T-cell response in the lung parenchyma and contributes to disease progression.Tuberculous pneumonia, necrotic granulomatous lesions, and bacterial dissemination characterize severe forms of mycobacterial infection. 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. 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)-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 IFN production. 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. (AU)

• Processo FAPESP: 15/20432-8 - Intervenção em vias de sinalização associadas ao reconhecimento de dano celular visando reduzir a patologia das formas graves de malária e tuberculose
• Beneficiário: Maria Regina D'Império Lima
• Modalidade de apoio: Auxílio à Pesquisa - Temático