PD-1 Expression and Cytokine Secretion Profiles of Mycobacterium tuberculosis-Specific CD4+ T-Cell Subsets; Potential Correlates of Containment in HIV-TB Co-Infection

Abstract

HIV co-infection is an important risk factor for tuberculosis (TB) providing a powerful model in which to dissect out defective, protective and dysfunctional Mycobacterium tuberculosis (MTB)-specific immune responses. To identify the changes induced by HIV co-infection we compared MTB-specific CD4+ responses in subjects with active TB and latent TB infection (LTBI), with and without HIV co-infection. CD4+ T-cell subsets producing interferon-gamma (IFN-γ), interleukin-2 (IL-2) and tumour necrosis factor-alpha (TNF-α) and expressing CD279 (PD-1) were measured using polychromatic flow-cytometry. HIV-TB co-infection was consistently and independently associated with a reduced frequency of CD4+ IFN-γ and IL-2-dual secreting T-cells and the proportion correlated inversely with HIV viral load (VL). The impact of HIV co-infection on this key MTB-specific T-cell subset identifies them as a potential correlate of mycobacterial immune containment. The percentage of MTB-specific IFN-γ-secreting T-cell subsets that expressed PD-1 was increased in active TB with HIV co-infection and correlated with VL. This identifies a novel correlate of dysregulated immunity to MTB, which may in part explain the paucity of inflammatory response in the face of mycobacterial dissemination that characterizes active TB with HIV co-infection.

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

“…In our study, we showed that IFN-γ single positive mycobacteria-specific CD4+ T cells were enriched in a late differentiated memory subset, a subset more susceptible to HIV infection (13). Moreover, elevated levels of PD-1 have been reported in IFN-γ single positive Mtb-specific CD4+ T cells (compared to more polyfunctional cells) (14), so monofunctional cells could conceivably be more prone to depletion and/or anergy. Further experiments, assessing the expression of β-chemokines, CCR5, inhibitory receptors and pro-survival molecules could help define whether Mtb-specific CD4+ T cells endowed with different cytokine secretion profiles are differentially permissive to HIV and/or exhibit different susceptibility to anergy or survival.…”

Immune checkpoint blockade in infectious diseases

“…However, PD-1-expression levels on total CD4 + T cells from individuals with active infection were only slightly higher than cells from healthy donors 102 . Notably, HIV-TB co-infection was consistently and independently associated with a reduced frequency of CD4 + IFN-γ and IL-2-dual secreting T cells and the proportion correlated inversely with HIV RNA in plasma 101 .…”

“…TB-specific CD4 + T cell responses in individuals with active TB infection were found to produce IFN-γ, IL-2 and TNF and express PD-1 101 . However, PD-1-expression levels on total CD4 + T cells from individuals with active infection were only slightly higher than cells from healthy donors 102 .…”

Deregulated lncRNAs in B Cells from Patients with Active Tuberculosis

“…Effective cell-mediated immune response plays an essential role in the host defense against intracellular pathogen Mtb[ 4 , 5 ]. Immunity to TB is still understood to be driven and maintained by T-cell derived immune response [ 6 ].…”