Characterization of Mycobacterium tuberculosis-Specific Th22 Cells and the Effect of Tuberculosis Disease and HIV Coinfection

Abstract

The development of a highly effective tuberculosis (TB) vaccine is likely dependent on our understanding of what constitutes a protective immune response to TB. Accumulating evidence suggests that CD4⁺ T cells producing IL-22, a distinct subset termed "Th22" cells, may contribute to protective immunity to TB. Thus, we characterized Mycobacterium tuberculosis-specific Th22 (and Th1 and Th17) cells in 72 people with latent TB infection or TB disease, with and without HIV-1 infection. We investigated the functional properties (IFN-γ, IL-22, and IL-17 production), memory differentiation (CD45RA, CD27, and CCR7), and activation profile (HLA-DR) of M. tuberculosis-specific CD4⁺ T cells. In HIV-uninfected individuals with latent TB infection, we detected abundant circulating IFN-γ-producing CD4⁺ T cells (median, 0.93%) and IL-22-producing CD4⁺ T cells (median, 0.46%) in response to M. tuberculosis The frequency of IL-17-producing CD4⁺ T cells was much lower, at a median of 0.06%. Consistent with previous studies, IL-22 was produced by a distinct subset of CD4⁺ T cells and not coexpressed with IL-17. M. tuberculosis-specific IL-22 responses were markedly reduced (median, 0.08%) in individuals with TB disease and HIV coinfection compared with IFN-γ responses. M. tuberculosis-specific Th22 cells exhibited a distinct memory and activation phenotype compared with Th1 and Th17 cells. Furthermore, M. tuberculosis-specific IL-22 was produced by conventional CD4⁺ T cells that required TCR engagement. In conclusion, we confirm that Th22 cells are a component of the human immune response to TB. Depletion of M. tuberculosis-specific Th22 cells during HIV coinfection may contribute to increased risk of TB disease.