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

Abstract

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^- (Th1*) 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 Th1* CD4⁺ T cells rather than major changes in the number or function of circulating CD4⁺ T cells.