Mice infected for 60 days with Mycobacterium tuberculosis were treated with aerosolized XCL1-targeting small interfering RNA (siRNA) to induce local and transient suppression of XCL1/lymphotactin (an important chemokine in tuberculoid granuloma formation). The local pulmonary siRNA therapy resulted in a 50% decrease in the total amount of xcl1 gene transcripts at 3 days, and 40 to 50% protein suppression 3 and 5 days after treatment. Reduced XCL1 expression in the lungs was associated with decreased numbers of T lymphocytes, reduction in the IFN-gamma response, disorganized granulomatous lesions, and higher fibrosis when compared with control mice treated with either PBS or nontargeting siRNA. This indicates that a transient but strong modulation of the production of XCL1 in the lungs has a significant effect on the influx of IFN-gamma-secreting T cells, as well as local pathology, but without significantly altering containment of the infection.