Induction of TGF-β1 and TGF-β1–dependent predominant Th17 differentiation by group A streptococcal infection

Abstract

Recurrent group A Streptococcus (GAS) tonsillitis and associated autoimmune diseases indicate that the immune response to this organism can be ineffective and pathological. TGF-β1 is recognized as an essential signal for generation of regulatory T cells (Tregs) and T helper (Th) 17 cells. Here, the impact of TGF-β1 induction on the Tcell response in mouse nasal-associated lymphoid tissue (NALT) following intranasal (i.n.) infections is investigated. ELISA and TGF-β1-luciferase reporter assays indicated that persistent infection of mouse NALT with GAS sets the stage for TGF-β1 and IL-6 production, signals required for promotion of a Th17 immune response. As predicted, IL-17, the Th17 signature cytokine, was induced in a TGF-β1 signaling-dependent manner in single-cell suspensions of both human tonsils and NALT. mice. These experiments link specific induction of TGF-β1 by a bacterial infection to an in vivo Th17 immune response and show that this cellular response is sufficient for protection against GAS. The association of a Th17 response with GAS infection reveals a potential mechanism for destructive autoimmune responses in humans.

Toll-like receptor-mediated adjuvanticity and immunomodulation in dendritic cells: Implications for peptide vaccines

“…Th17 immune responses have recently been demonstrated to be important in protection against group A streptococcal infection. 43 Together with our findings indicating Pam3CSK4 as a potential Th17-promoting TLR agonist, this may explain the success in preclinical studies of various lipidated-group A streptococcal peptides in protecting against strep A challenge and throat colonization. 44,45 Using various MAPK inhibitors (JNK, p38 MAPK and ERK) we have demonstrated the importance of p38 MAPK and ERK signaling pathways in IL-12p70 and IL-12p40 production in DCs induced by stimulation with individual TLR agonists and previously following dual TLR stimulation.…”

Nasal Immunity to Staphylococcal Toxic Shock Is Controlled by the Nasopharynx-Associated Lymphoid Tissue

“…Activation and expansion of T cells also results in Th17 differentiation within the NALT. Secretion of IL-17 is linked to bacterial clearance in the NALT and lungs of infected mice (46,48). Within the NALT, most newly expanded DCs tend to segregate alongside T cells (14).…”

Generation of Th17 cells in response to intranasal infection requires TGF-β1 from dendritic cells and IL-6 from CD301b + dendritic cells

“…Th17 cells are also generated during intranasal (i.n.) infection by Streptococcus pyogenes, and TGF-β1 receptor signaling and IL-6 are involved (6,7). However, Th17 cell formation in the small intestine does not depend on TGF-β1 (8) and requires IL-1β but not IL-6 (9).…”