Mycobacteria-responsive sonic hedgehog signaling mediates programmed death-ligand 1- and prostaglandin E2-induced regulatory T cell expansion

Abstract

CD4+CD25+FoxP3+ regulatory T cells (Tregs) are exploited by mycobacteria to subvert the protective host immune responses. The Treg expansion in the periphery requires signaling by professional antigen presenting cells and in particularly dendritic cells (DC). However, precise molecular mechanisms by which mycobacteria instruct Treg expansion via DCs are not established. Here we demonstrate that mycobacteria-responsive sonic hedgehog (SHH) signaling in human DCs leads to programmed death ligand-1 (PD-L1) expression and cyclooxygenase (COX)-2-catalyzed prostaglandin E2 (PGE2) that orchestrate mycobacterial infection-induced expansion of Tregs. While SHH-responsive transcription factor GLI1 directly arbitrated COX-2 transcription, specific microRNAs, miR-324-5p and miR-338-5p, which target PD-L1 were downregulated by SHH signaling. Further, counter-regulatory roles of SHH and NOTCH1 signaling during mycobacterial-infection of human DCs was also evident. Together, our results establish that Mycobacterium directs a fine-balance of host signaling pathways and molecular regulators in human DCs to expand Tregs that favour immune evasion of the pathogen.

IL-1β, But Not Programed Death-1 and Programed Death Ligand Pathway, Is Critical for the Human Th17 Response to Mycobacterium tuberculosis

“…This discrepancy might be due to the fact that previous report focused on active disease where prolonged infection can enhance additional co-stimulatory molecules that might not be present during the earlier phases of stimulation. For example, APCs from active disease express both the co-stimulatory molecules PD-L1 and PD-L2 (31), whereas our current data and previous reports show that DCs from healthy individuals stimulated with M. tuberculosis both at the transcript level as well as the protein level induce only PD-L1 and not PD-L2 (30, 33). It is essential to note that we have used γ-irradiated M. tuberculosis or M. tuberculosis -derived cell wall, cell membrane, or cytoplasmic fractions in our experiments, and these conditions may not completely mimic in vivo situation of infection with live bacteria.…”

“…Several recent reports have indicated that PD-1–PD-L1/PD-L2 axis has a pivotal role in the regulation of T cell response to M. tuberculosis (29, 31, 33). Therefore, to decipher the role of PD-L1/PD-L2 in regulating Th17 response to M. tuberculosis , we first investigated the ability of M. tuberculosis and its different antigen fractions in modulating PD-L1 and PD-L2 expression on monocytes and DCs.…”

“…Recent data highlight the role of PD-1–PD-L1/PD-L2 axis in modulating regulatory T cell (Treg) and Th1 response to M. tuberculosis (29–33). Whether this pathway also regulates Th17 response to M. tuberculosis is not known.…”

COX-2 Inhibition Reduces Brucella Bacterial Burden in Draining Lymph Nodes

“…Thus, we hypothesize that infection stimulates regulatory/suppressor T-cells that can favor bacterial persistence through the secretion of IL-10. A similar effect has been described during Mycobacterium tuberculosis infection where COX-2/PGE 2 axis stimulates T-reg expansion (Garg et al, 2008; Holla et al, 2016). Thereby, T-reg accumulation contributes to the decrease of bacterial clearance in infected mice (Kursar et al, 2007).…”

The Yin and Yang of regulatory T cells in infectious diseases and avenues to target them

“…Bacteria stimulate Treg expansion by several mutually nonexclusive mechanisms. Mycobacterium tuberculosis ‐mediated Treg expansion in humans implicate PD‐1‐PD‐L1/PD‐L2 axis and COX‐2‐catalysed Prostaglandin E2 (PGE2) (Garg et al, ; Holla et al, ; Periasamy et al, ; Singh, Mohan, Dey, & Mitra, ; Trinath, Maddur, Kaveri, Balaji, & Bayry, ). Blockade of these pathways in vitro not only abrogated Treg expansion but also reciprocally enhanced IFN‐γ responses (Periasamy et al, ; Singh et al, ; Stephen‐Victor et al, ; Stephen‐Victor et al, ).…”