HIV impairs and exploits pulmonary Th17 and Th22 cell-mediated immune responses to Mycobacterium tuberculosis

TL;DR

HIV targets Th17 and Th22 immune cells, impairing the body's ability to fight tuberculosis and possibly worsening the disease.

Contribution

This study identifies Th17 and Th22 cells as key players in HIV-Mtb co-infection and shows how HIV exploits Th17 cells while impairing Th22 immunity.

Findings

Th17 cells are a major HIV reservoir in co-infected mice and are increased in TB-infected lungs.

HIV reduces Th22 cells and suppresses protective cytokine responses to Mtb.

HIV co-infection disrupts Mtb-induced Th17 pathways in the lungs.

Abstract

Tuberculosis (TB) kills an estimated 1.25 million people annually and is the leading cause of death in people with HIV (PWH) (1). The CD4+ T helper (Th) populations play significant roles in protective immunity to Mycobacterium tuberculosis (Mtb) and are essential hosts for HIV pathogenesis. Emerging evidence in blood and gastrointestinal mucosa of PWH suggests that, among Th cells, Th17 and Th22 may be preferentially depleted during HIV infection. Targeting of Th17 and Th22 cells by HIV could pose important and poorly understood risks for Mtb containment in those with co-infection. Mtb-driven activation of Th17 and Th22 immunity may also contribute to HIV proliferation and persistence. We employed a humanized mouse model of co-infection to assess changes in Th17 and Th22 frequency and function due to infection with HIV, Mtb, or both. In infected mice, Th17 cells were the predominant host for HIV in spleen and shown to be a source of HIV replication in pulmonary TB granulomas. Th17 cells were increased in lung of mice with TB or TB-HIV. Conversely, Th22 cells were reduced in mice with HIV or TB-HIV. Mtb infection increased the viral load in lungs of co-infected mice while HIV suppressed the pulmonary Th17 family cytokine response to Mtb including IL-6, IL-22, IL-23, and IL-1β. Differential transcriptome assessment demonstrated that HIV co-infection disrupted Th17 pathways activated by Mtb in lung. Overall, these results suggest that HIV may compromise Th22 immunity and exploit Th17 cells to promote viral pathogenesis in the setting of Mtb and HIV co-infection.

Tuberculosis (TB), caused by the bacteria Mycobacterium tuberculosis (Mtb), is the world’s leading cause of death by infectious disease, as well as the leading cause of death in people with HIV. The cytokines interleukin (IL)-17 and IL-22 are chemical messengers that are essential for a protective immune response to Mtb infections and tissue repair following bacterial clearance, respectively. The CD4+ T cell subsets that are important sources of these cytokines, Th17 and Th22 cells, are also primary targets for HIV infection at mucosal surfaces like the gut. Our work reveals Th17 as important HIV viral reservoirs in organs during Mtb and HIV co-infection, exhibiting defective immune signals compared to Mtb single infection in the humanized mouse model. Th22 responses were also decreased by HIV as early as nine days after infection in mice with either HIV or Mtb-HIV infection. These results have potential applications for future TB therapeutic vaccine design and may implicate possible targets to augment TB therapy.

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