<p>Bacterial superantigens are potent immune activators that trigger T cell proliferation and intensive release of cytokines, leading to toxic shock syndrome. Also, they impair host immune responses, increasing bacterial carriage and transmission. Several studies proposed that superantigens can induce regulatory T (Treg) cells, which may suppress immune responses against bacterial infection. However, the mechanism of Treg cell induction by superantigens is still elusive. We here demonstrated that streptococcal pyrogenic exotoxin A (SPEA) promoted human CD4⁺CD25⁺Foxp3⁺ T cell induction in a dose- and time-dependent manner and the induction required antigen-presenting cells (APCs). SPEA-induced CD4⁺CD25⁺ T cells could suppress allogeneic T cell proliferation and IL-2 secretion. Flow cytometric analyses demonstrated high expression of TNFR2 on SPEA-induced CD4⁺CD25⁺Foxp3⁺ T cells. Blocking the interaction between TNF-⍺ and TNFR2 reduced SPEA-induced CD25⁺Foxp3⁺ Treg cells. Our present study suggests a mechanism that the TNF-⍺ and TNFR2 axis is required for the induction of human CD4⁺CD25⁺Foxp3⁺ Treg cells by SPEA, which implicates a potential strategy to enhance the clearance of Group A streptococcus infection through reducing Treg cell induction by the inhibition of TNFR2 signaling.</p>