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

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]

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

• 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
• Modalidade de apoio: 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
• Modalidade de apoio: Auxílio à Pesquisa - Regular