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 human immunodeficiency virus-1 (HIV-1) is a major risk factor for tuberculosis (TB), and a better understanding of HIV-induced alterations of Mycobacterium tuberculosis (Mtb)-specific CD4+ T cells that leads to failed host resistance may provide insight into protective T cell immunity to TB. Eighty-six participants from a TB-endemic setting, either HIV-infected or -uninfected and with latent or active TB, were screened using Mtb-specific MHC class II tetramers. We examined the phenotype as well as function of ex vivo Mtb-specific tetramer+CD4+ T cells using flow cytometry. The numbers of Mtb-specific tetramer+CD4+ T cells were relatively well maintained in HIV-infected persons with active TB, despite severe immunodeficiency. However, while HIV-uninfected persons with latent TB infection exhibited ex vivo Mtb-specific CD4+ T cells predominantly of a CXCR3+CCR6+CCR4- (Th1*) phenotype; active TB or HIV infection was associated with a contraction of this subset. Nevertheless, in individuals with active TB and/or HIV infection, circulating ex vivo Mtb-specific CD4+ T cells did not display defects in exhaustion or polyfunctionality compared to 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.

Th1, Th17, and Th1Th17 Lymphocytes during Tuberculosis: Th1 Lymphocytes Predominate and Appear as Low-Differentiated CXCR3+CCR6+ Cells in the Blood and Highly Differentiated CXCR3+/−CCR6− Cells in the Lungs

“…A similar comparison has recently been performed by Strickland et al (50). They analyzed X3/R6/CCR4 expression by M. tuberculosis-specific CD4 + lymphocytes in TB patients and LTBI subjects and found that TB patients exhibited decreased X3 + R6 + populations and expanded X3 2 R6 2 populations.…”

“…Additionally, there are several methodological differences between the two studies that can account for the discrepancy. Particularly, Strickland et al (50) identified M. tuberculosisspecific lymphocytes using tetramer staining (i.e., detected cells irrespective of their ability to produce cytokines). Our analysis of Th1 cells was specifically focused on IFN-g + IL-17 2 lymphocytes.…”

“…Our analysis of Th1 cells was specifically focused on IFN-g + IL-17 2 lymphocytes. Strickland et al (50) examined CD4 + lymphocytes specific to ESAT-6/CFP-10 Ags. In our study, cells responding to all Ags present in PPD were analyzed.…”

The Rate of CD4 T Cell Entry into the Lungs during Mycobacterium tuberculosis Infection Is Determined by Partial and Opposing Effects of Multiple Chemokine Receptors

“…CCR6 is not found on M. tuberculosis-specific CD4 T cells in mice. In contrast, in humans and nonhuman primates, peptide-specific CD4 T cells coexpress CXCR3 and CCR6 (27,(31)(32)(33)(34). CXCR5 expression seems to display the opposite trend in expression between species.…”

Assessment of an ultra-sensitive IFNγ immunoassay prototype for latent tuberculosis diagnosis

“…However, the QFT results are considered "indeterminate" when the positive control values are low or when there is a high background response to the negative control. Indeterminate results are often associated with immunodeficiency due to lymphopenia, HIV, or immunosuppressive treatments [14][15][16][17][18][19]. This immunodeficiency reduces the T lymphocyte population and, consequently, the amount of IFN␥ secreted is decreased.…”