PD-1 Expression on Mycobacterium tuberculosis-Specific CD4 T Cells Is Associated With Bacterial Load in Human Tuberculosis

Abstract

Persistent antigen stimulation in chronic infections has been associated with antigen-specific T cell dysfunction and upregulation of inhibitory receptors, including programmed cell death protein 1 (PD-1). Pulmonary tuberculosis (TB) disease is characterized by high levels of Mycobacterium tuberculosis (Mtb), yet the relationship between bacterial load, PD-1 expression, and Mtb-specific T cell function in human TB has not been well-defined. Using peripheral blood samples from adults with LTBI and with pulmonary TB disease, we tested the hypothesis that PD-1 expression is associated with bacterial load and functional capacity of Mtb-specific T cell responses. We found that PD-1 was expressed at significantly higher levels on Th1 cytokine-producing Mtb-specific CD4 T cells from patients with smear-positive TB, compared with smear-negative TB and LTBI, which decreased after completion of anti-TB treatment. By contrast, expression of PD-1 on Mtb-specific CD8 T cells was significantly lower than on Mtb-specific CD4 T cells and did not differ by Mtb infection and disease status. In vitro stimulation of PBMC with Mtb antigens demonstrated that PD-1 is induced on proliferating Mtb-specific CD4 T cells and that Th1 cytokine production capacity is preferentially maintained within PD-1+ proliferating CD4 T cells, compared with proliferating Mtb-specific CD4 T cells that lack PD-1 expression. Together, these data indicate that expression of PD-1 on Mtb-specific CD4 T cells is indicative of mycobacterial antigen exposure and identifies a population of effector cells with Th1 cytokine production capacity. These studies provide novel insights into the role of the PD-1 pathway in regulating CD4 and CD8 T cell responses in Mtb infection and provide rationale for future studies to evaluate PD-1 expression on antigen-specific CD4 T cells as a potential biomarker for bacterial load and treatment response in human TB.

PD‐1‐expressing MAIT cells from patients with tuberculosis exhibit elevated production of CXCL13

“…Expression of PD‐1 on T cells, MAIT cells and NK cells from patients with TB was elevated, and blockage of PD‐1 and/or its ligands improves functions of T cells, MAIT cells and NK cells . PD‐1 expression on Mtb ‐specific CD4 T cells correlates with bacterial load and decreases after successful anti‐TB drug treatment . Bronchoalveolar lavage from patients with military TB had significantly higher PD‐1 + T cells with diminished production of IFN‐γ and TNF‐α .…”

“…15,16,[21][22][23] PD-1 expression on Mtb-specific CD4 T cells correlates with bacterial load and decreases after successful anti-TB drug treatment. 24,25 Bronchoalveolar lavage from patients with military TB had significantly higher PD-1 + T cells with diminished production of IFN-γ and TNF-α. 26 Although PD-1 −/− mice had highly enhanced Th1 responses during Mtb infection, they showed severe and lethal immunopathology.…”

PD-1 modulating Mycobacterium tuberculosis-specific polarized effector memory T cells response in tuberculosis pleurisy

“…Without doubt, these data raise questions regarding the role of PD‐1 on T cells. One possible explanation for the observation is that signal transduction via the PD‐1 pathway during chronic viral infections are inherently different from those that occur during chronic bacterial infections . PD‐1 is not a marker of exhaustion in T cells in TB is that previous studies focused on viral‐specific CD8 T cells.…”

“…One possible explanation for the observation is that signal transduction via the PD-1 pathway during chronic viral infections are inherently different from those that occur during chronic bacterial infections. 22,36,37 PD-1 is not a marker of exhaustion in T cells in TB is that previous studies focused on viralspecific CD8 T cells. Lineage-specific differences may result from the utilization of different signaling pathways in the T-cell subsets.…”

Persistent DNA Hyper-methylation Dampens Host Anti-Mycobacterial Immunity

“…HIV increases the likelihood of anergy 34 , but in some cohorts up to 46% of HIV-negative TB cases are anergic 40 . Modern immune analysis has characterized TB-induced immune exhaustion demonstrating that TB patients have decreased IFN-γ, IL-2 and proliferative capacity with an increase in immune checkpoint inhibitors, such as PD-1, TIM3 and CTLA-4 18,19,41,42 . In addition to limiting critical cytokines, such as IFN-γ, previous studies have demonstrated that immune cells from TB patients to have downstream defects in cell signaling including decreased IFN-γ-inducible gene expression 43,44 .…”