Phosphorylated STAT3 and PD‐1 regulate IL‐17 production and IL‐23 receptor expression in Mycobacterium tuberculosis infection

Abstract

SUMMARY We studied the factors that regulate IL-23 receptor expression and IL-17 production in human tuberculosis infection. Mycobacterium tuberculosis (M. tb)-stimulated CD4+ cells from tuberculosis patients secreted less IL-17 than did CD4+ cells from healthy tuberculin reactors (PPD+). M. tb cultured monocytes from tuberculosis patients and PPD+ donors expressed equal amounts of IL-23p19 mRNA and protein, suggesting that reduced IL-23 production is not responsible for decreased IL-17 production by tuberculosis patients. Freshly isolated and M. tb- stimulated CD4+ cells from tuberculosis patients had reduced IL-23 receptor and phosphorylated STAT3 (pSTAT3) expression, compared to PPD+ donors. STAT3 siRNA reduced IL-23 receptor expression, and IL-17 production by CD4+ cells from PPD+ donors. Tuberculosis patients had increased number of PD-1+ T cells compared to healthy PPD+ individuals. Anti-PD-1 antibody enhanced pSTAT3 and IL-23R expression and IL-17 production by M. tb cultured CD4+ cells of tuberculosis patients. Anti-tuberculosis therapy decreased PD-1 expression, increased IL-17 and IFN-γ production and pSTAT3, IL-23R expression. These findings demonstrate that increased PD-1 expression and decreased pSTAT3 expression reduces IL-23 receptor expression and IL-17 production by CD4+ cells of tuberculosis patients.

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

“…Programed death ligand-1 signals via PD-1 on CD4 + T cells, and recently it was reported that Mycobacterium -induced PD-1 coordinates suppression of Th17 response in tuberculosis patients (28). We confirm that M. tuberculosis significantly enhances the frequency of PD-1 + T cells in the DC/monocyte–CD4 + T cell cocultures (Figures 7A,D).…”

“…Recent reports in tuberculosis patients indicate that active disease and its severity are associated with low Th17 response (26, 27). Of note, anti-tuberculosis therapy is associated with enhanced Th17 response, suggesting that M. tuberculosis suppresses Th17 response as one of the immune evasion mechanisms (28). …”

Signal transducer and activator of transcription 3

“…(13). This was a surprising finding given that no such defect or infectious predilection is seen in AD-HIES despite the impaired capacity for RORγt upregulation(14). This observation might be partially explained by the recent finding that while unconventional T cells (which could have roles in anti-mycobacterial immunity) such as natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are reduced in AD-HIES, the MAIT at least express normal levels of ROR γt(15).…”

The IL-17-Th1/Th17 pathway: an attractive target for lung cancer therapy?

“…A causal relationship between PD-1 signaling and IL-17 response is suggested by the fact that tuberculosis patients were found to have increased numbers of PD-1+ T-cells compared with healthy individuals, and in this case, CD4+ T-cells secreted less IL-17 [195]. Overall, PD-L1 deficiency or blockade is suggested to play an important role in Th17 expansion, and the PD-L1/Th17 axis may be an important therapeutic target for cancer treatment.…”