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.

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