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

Chronic pulmonary inflammation marked predominantly by CD4(+)IFN-γ(+) 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-γ-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-γ-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.