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

We studied the factors that regulate IL-23 receptor expression and IL-17 production in human tuberculosis infection. Mycobacterium tuberculosis (M. tb)-stimulated CD4+ T cells from tuberculosis patients secreted less IL-17 than did CD4+ T 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+ T cells from tuberculosis patients had reduced IL-23 receptor and phosphorylated STAT3 (pSTAT3) expression, compared with cells from PPD+ donors. STAT3 siRNA reduced IL-23 receptor expression and IL-17 production by CD4+ T cells from PPD+ donors. Tuberculosis patients had increased numbers of PD-1+ T cells compared with healthy PPD+ individuals. Anti-PD-1 antibody enhanced pSTAT3 and IL-23R expression and IL-17 production by M. tb-cultured CD4+ T cells of tuberculosis patients. Anti-tuberculosis therapy decreased PD-1 expression, increased IL-17 and IFN-γ production and pSTAT3 and IL-23R expression. These findings demonstrate that increased PD-1 expression and decreased pSTAT3 expression reduce IL-23 receptor expression and IL-17 production by CD4+ T cells of tuberculosis patients.