HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis–Specific CD4+ T Cells

Abstract

HIV-infected persons are at greater risk of developing tuberculosis (TB) even before profound CD4 loss occurs, suggesting that HIV alters CD4+T cell functions capable of containing bacterial replication. An effective immune response to Mycobacterium tuberculosis likely relies on the development of a balanced CD4 response, where distinct CD4+T helper subsets act in synergy to control the infection. To define the diversity of Mtb-specific CD4+Th subsets and determine whether HIV infection impacts such responses, the expression of lineage-defining transcription factors T-bet, Gata3, RORγt and Foxp3 was measured in Mtb-specific CD4+T cells in HIV-uninfected (n=20) and HIV-infected individuals (n=20) with latent TB infection. Our results show that upon 5 day restimulation in vitro, Mtb-specific CD4+T cells from healthy individuals have the ability to exhibit a broad spectrum of T helper subsets, defined by specific patterns of transcription factor co-expression. These transcription factor profiles were skewed in HIV-infected individuals where the proportion of T-bethighFoxp3+ Mtb-specific CD4+T cells was significantly decreased (p=0.002) compared to HIV-uninfected individuals, a change that correlated inversely with HIV viral load (p=0.0007) and plasma TNF-α (p=0.027). Our data demonstrate an important balance in T helper subset diversity defined by lineage-defining transcription factor co-expression profiles that is disrupted by HIV infection and suggest a role for HIV in impairing TB immunity by altering the equilibrium of Mtb-specific CD4+T helper subsets.

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

“…HIV-induced alteration of chemokine receptor expression has been reported previously (37, 38). These alterations during HIV infection may alter the homing potential of Mtb-specific CD4+ T cells or affect their T helper lineage commitment, as we reported previously (11). Moreover, recent reports demonstrate that the homing potential and Th differentiation status of Mtb-specific cells can dramatically influence immune protection against TB (39, 40).…”

“…However, TB risk is significantly elevated even in HIV-infected persons with well-preserved CD4+ T cell counts (during the early phase of infection or after immune-restoring ART), suggesting that HIV may also induce qualitative defects in Mtb-specific CD4+ T cells. Indeed, alterations in the polyfunctional capacity (8, 9), memory profile (10) and lineage differentiation (11) of Mtb-specific CD4+ T cells have been previously reported. Moreover, HIV promotes systemic immune activation (12) and cell exhaustion (13).…”

CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

“…More broadly, both virus-specific CD4 + T cell responses and unrelated CD4 + T cell responses display a pattern of transcription factor and differentiation marker expression that suggest there are altered T helper subset lineage decisions during chronic viral infection in mice 19,52 . Recent work has also demonstrated that these lineage decisions are plastic, and CD4 + T cells can retain the ability to acquire functions of other subsets 11,53 .…”

Selective reduction of IFN-γ single positive mycobacteria-specific CD4+ T cells in HIV-1 infected individuals with latent tuberculosis infection

“…It has been proposed that, notwithstanding overall CD4+ T cell depletion, HIV may also induce qualitative changes in CD4+ T cell function, further weakening protective immune responses to Mtb. Alteration of the polyfunctional capacity (5, 6), memory profile (7) and lineage differentiation (8) of Mtb-specific CD4+ T cells have been reported. Most work has reported the effect of HIV on TB immune response during active TB; and fewer studies have compared the attributes of mycobacterial-specific CD4+ T cells in the context of latent tuberculosis infection in HIV-uninfected and HIV-infected persons (2, 3, 8, 9).…”