HIV Interferes with the Dendritic Cell–T Cell Axis of Macrophage Activation by Shifting Mycobacterium tuberculosis–Specific CD4 T Cells into a Dysfunctional Phenotype

Abstract

HIV coinfection is the greatest risk factor for transition of latent Mycobacterium tuberculosis infection into active tuberculosis (TB). Epidemiological data reveal both the reduction and the impairment of M. tuberculosis-specific CD4 T cells, although the cellular link and actual mechanisms resulting in immune impairment/suppression need further characterization. M. tuberculosis-specific CD4 T cells play a central role in development of protective immunity against TB, in which they participate in the activation of macrophages through the dendritic cell (DC)-T cell axis. Using an in vitro priming system for generating Ag-specific T cells, we explored if HIV-M. tuberculosis-infected (coinfected) human DCs can dysregulate the M. tuberculosis-specific CD4 T cell phenotype and functionality and subsequently mediate the failure to control M. tuberculosis infection in macrophages. After coculture with coinfected DCs, M. tuberculosis Ag-specific CD4 T cells lost their ability to enhance control of M. tuberculosis infection in infected macrophages. Coinfection of DCs reduced proliferation of M. tuberculosis Ag-specific CD4 T cells without affecting their viability, led to increased expression of coinhibitory factors CTLA-4, PD-1, and Blimp-1, and decreased expression of costimulatory molecules CD40L, CD28, and ICOS on the T cells. Expression of the regulatory T cell markers FOXP3 and CD25, together with the immunosuppressive cytokines TGF-b and IL-10, was also significantly increased by coinfection compared with M. tuberculosis single infection. Our data suggest a pattern in which HIV, through its effect on DCs, impairs the ability of M. tuberculosis-specific CD4 T cells to maintain a latent TB within human macrophages, which could play an early role in the subsequent development of TB.

Tuberculosis Antigen-Specific T-Cell Responses During the First 6 Months of Antiretroviral Treatment

“…However, the incidence of tuberculosis remains higher in HIV-1–infected persons despite ART (compared to those HIV-1 uninfected), regardless of the duration of ART or CD4 count [2]. This could be due to depletion of Mycobacterium tuberculosis -specific T cells early during HIV-1 infection [3], as well as impairment of function of these antigen-specific CD4 T cells [4]. Increased ART-mediated immunity correlates with expansion of early differentiated (central memory) T-cell responses overall [5–7].…”

Mycobacterium tuberculosis and HIV coinfection : Effects on innate immunity and strategies to boost the immune response

“…Furthermore, our group has recently shown that HIV coinfected dendritic cells induce increased expression of co-inhibitory molecules on Mtb Agspecific T cells, along with increased production of IL-10 and TGF-β. These suppressive Mtb Ag-specific T cells failed to control Mtb in macrophages (235). Without the activation of T cells and their production of IFN-γ, the enhancement of macrophage immunity against Mtb is impaired, and need to be activated in other ways during an HIV coinfection.…”

Antiretroviral treatment-induced decrease in immune activation contributes to reduced susceptibility to tuberculosis in HIV-1-TB co-infected persons

“…This could be due to depletion of Mycobacterium tuberculosis (Mtb) specific T cells early during HIV-1 infection (5) as well as impairment of function of these antigen-specific CD4 T cells (6).…”

“…Where j represents subjects -j∈[1,Npeople], Npeople= 30, and i represents time points -i∈[0,1,3,6].Time (here being the follow-up rounds) is treated as a discrete categorical variable. This allows us to model the effect of time on analyte progression without imposing parametric specifications on the shape of the relationship between time and analytes.…”