CCR4-dependent reduction in the number and suppressor function of CD4Foxp3 cells augments IFN-γ-mediated pulmonary inflammation and aggravates tuberculosis pathogenesis.

Chronic pulmonary inflammation marked predominantly by CD4IFN-γ cells is the hallmark of tuberculosis pathogenesis in immunocompetent adults, who are substantially affected by this disease. Moreover, CD4Foxp3 cell-mediated suppression contributes to infection susceptibility. We addressed the role of CD4Foxp3 cells in tuberculosis pathogenesis, because this aspect has not been addressed during chronic infection. We targeted CCR4, which induces the influx of CD4Foxp3 cells into the lungs. CCR4 mice exhibited a lower frequency of CD4Foxp3 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-γ-mediated immune response associated with apparent tuberculosis pathogenesis and susceptibility. In addition, CCR4 mice exhibited a decrease in the suppressor function of CD4Foxp3 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 CD4Foxp3 cells play a time-dependent role in tuberculosis and highlight that CCR4 plays a critical role in the balance of IFN-γ-mediated inflammation by regulating the influx and function of CD4Foxp3 cells. Our findings are translationally relevant, as CD4Foxp3 cells or CCR4 could be a target for immunotherapy, considering the heterogeneity of tuberculosis in immunocompetent adults.