LoadHumans Is Associated with Mycobacterial -Specific T Cell Responses in tuberculosis Mycobacterium Functional Capacity of

High Ag load in chronic viral infections has been associated with impairment of Ag-specific T cell responses; however, the relationship between Ag load in chronic Mycobacterium tuberculosis infection and functional capacity of M. tuberculosis -specific T cells in humans is not clear. We compared M. tuberculosis -specific T cell-associated cytokine production and proliferative capacity in peripheral blood from adults with progressively higher mycobacterial loads—that is, persons with latent M. tuberculosis infection (LTBI), with smear-negative pulmonary tuberculosis (TB), and smear-positive TB. Patients with smear-positive TB had decreased polyfunctional IFN- g + IL-2 + TNF- a + and IL-2–producing specific CD4 T cells and increased TNF- a single-positive cells, when compared with smear-negative TB and LTBI. TB patients also had increased frequencies of M. tuberculosis -specific CD8 T cells, compared with LTBI. M. tuberculosis -specific CD4 and CD8 T cell proliferative capacity was profoundly impaired in individuals with smear-positive TB, and correlated positively with ex vivo IFN- g + IL-2 + TNF- a + CD4 T cells, and inversely with TNF- a single-positive CD4 T cells. During 6 mo of anti-TB treatment, specific IFN- g + IL-2 + TNF- a + CD4 and CD8 T cells increased, whereas TNF- a and IFN- g single-positive T cells decreased. These results suggest progressive impairment of M. tuberculosis -specific T cell responses with increasing mycobacterial load and recovery of responses during therapy. Furthermore, these data provide a link between specific cytokine-producing subsets and functional capacity of M. tuberculosis -specific T cells, and between the presence of specific CD8 T cells ex vivo and active TB disease. These data have potentially significant applications for the diagnosis of TB and for the identification of T cell correlates of TB disease progression. The Journal of Immunology , 2011, 187: 2222–2232. by the Dunn’s posttest. If significance was found ( p , 0.05), pairwise comparisons were analyzed using the Mann–Whitney U test. The Fisher’s exact test was used to assess differences in the frequency of recognition of M. tuberculosis -specific CD8 T cell responses among the three groups. For longitudinal analysis of M. tuberculosis -specific T cell responses on anti- TB treatment, differences between time points were first assessed using the Friedman test, followed by the Dunn’s posttest. If significance was found ( p , 0.05), pairwise comparisons were analyzed using the Wilcoxon matched pairs test. Correlations were assessed using Spearman’s rank correlation.