Abstract
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.
Highlights
The treatment of tuberculosis remains a great challenge, and researchers are attempting to develop new vaccines that can confer stronger protection than the BCG vaccine and prevent the progression of active pulmonary disease in adults[1]
At 15 days of infection, CCR4-deficient animals exhibited improved resistance compared with their WT counterparts (Fig. 1a), there was no difference in the number of bacilli quantified in the spleens of these mice (Fig. 1b)
The absence of CCR4 resulted in exacerbated susceptibility to M. tuberculosis infection at 70 days, as the colony forming unit (CFU) counts in the lungs and spleens were significantly higher in CCR4-deficient mice than in their WT counterparts (Fig. 1a, b)
Summary
The treatment of tuberculosis remains a great challenge, and researchers are attempting to develop new vaccines that can confer stronger protection than the BCG vaccine and prevent the progression of active pulmonary disease in adults[1]. With the first observations of HIV (human immunodeficiency virus) infection in. 1981, there was a remarkable increase in the number of individuals co-infected with HIV and Mycobacterium tuberculosis[2]. The majority of infected subjects who develop active tuberculosis worldwide are immunocompetent individuals[3]. The hallmark of the protective immune response against tuberculosis is the differentiation of INF-γproducing CD4+ cells and the activation of inflammatory M1 macrophages[4,5]. M. tuberculosis infection is a Official journal of the Cell Death Differentiation Association
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