Characterization of Mycobacterium tuberculosis-Specific Cells Using MHC Class II Tetramers Reveals Phenotypic Differences Related to HIV Infection and Tuberculosis Disease

A major challenge for the development of an effective vaccine against tuberculosis (TB) is that the attributes of protective CD4(+) T cell responses are still elusive for human TB. Infection with HIV type 1 is a major risk factor for TB, and a better understanding of HIV induced alterations of Mycobacterium tuberculosis specific CD4(+) T cells that leads to failed host resistance may provide insight into protective T cell immunity to TB. A total of 86 participants from a TB-endemic setting, either HIV-infected or uninfected and with latent or active TB (aTB), were screened using M. tuberculosis specific MHC class II tetramers. We examined the phenotype as well as function of ex vivo M. tuberculosis specific tetramer(+)CD4(+) T cells using flow cytometry. The numbers of M. tuberculosis specific tetramer(+)CD4(+) T cells were relatively well maintained in HIV-infected persons with aTB, despite severe immunodeficiency. However, although HIV-uninfected persons with latent TB infection exhibited ex vivo M. tuberculosis specific CD4(+) T cells predominantly of a CXCR3(+)CCR6(+)CCR4(-) (Thl*) phenotype, aTB or HIV infection was associated with a contraction of this subset. Nevertheless, in individuals with aTB and/or HIV infection, circulating ex vivo M. tuberculosis specific CD4(+) T cells did not display defects in exhaustion or polyfunctionality compared with healthy HIV-uninfected individuals with latent TB infection. Collectively, these data suggest that increased susceptibility to TB disease could be related to a loss of circulating Thl* CD4(+) T cells rather than major changes in the number or function of circulating CD4(+) T cells.