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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

CCR4-dependent reduction in the number and suppressor function of CD4(+)Foxp3(+) cells augments IFN-gamma-mediated pulmonary inflammation and aggravates tuberculosis pathogenesis

Texto completo
Autor(es):
Bertolini, Thais B. [1] ; Pineros, Annie R. [1] ; Prado, Rafael Q. [1] ; Gembre, Ana Flavia [1] ; Ramalho, Leandra N. Z. [2] ; Alves-Filho, Jose Carlos [3] ; Bonato, Vania L. D. [1]
Número total de Autores: 7
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Ribeirao Preto, SP - Brazil
[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pathol, Ribeirao Preto, SP - Brazil
[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto, SP - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: CELL DEATH & DISEASE; v. 10, DEC 21 2018.
Citações Web of Science: 0
Resumo

Chronic pulmonary inflammation marked predominantly by CD4(+) IFN-gamma(+) cells is the hallmark of tuberculosis pathogenesis in immunocompetent adults, who are substantially affected by this disease. Moreover, CD4(+) Foxp3(+) cell-mediated suppression contributes to infection susceptibility. We addressed the role of CD4(+) Foxp3(+) cells in tuberculosis pathogenesis, because this aspect has not been addressed during chronic infection. We targeted CCR4, which induces the influx of CD4(+) Foxp3(+) cells into the lungs. CCR4(-/-) mice exhibited a lower frequency of CD4(+) Foxp3(+) cells at 15, 30, and 70 days of infection than their wild-type counterparts. However, only at 70 days of infection was an exacerbated IFN-gamma-mediated immune response associated with apparent tuberculosis pathogenesis and susceptibility. In addition, CCR4(-/-) mice exhibited a decrease in the suppressor function of CD4(+) Foxp3(+) cells. Adoptive transfer of Foxp3(+) cells into infected CCR4(-/-) mice restored pulmonary inflammation and bacterial load to levels observed in wild-type mice. Our findings suggest that CD4(+) Foxp3(+) cells play a time-dependent role in tuberculosis and highlight that CCR4 plays a critical role in the balance of IFN-gamma-mediated inflammation by regulating the influx and function of CD4(+) Foxp3(+) cells. Our findings are translationally relevant, as CD4(+) Foxp3(+) cells or CCR4 could be a target for immunotherapy, considering the heterogeneity of tuberculosis in immunocompetent adults. (AU)

Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
Beneficiário:Fernando de Queiroz Cunha
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 11/09702-2 - Avaliação do papel das células dendríticas na diferenciação de populações de células CD4+ em animais com capacidade diferente de elaborar resposta imune celular contra Mycobacterium tuberculosis
Beneficiário:Vânia Luiza Deperon Bonato
Linha de fomento: Auxílio à Pesquisa - Regular