Induction of TGF-beta1 and TGF-beta1-dependent predominant Th17 differentiation by group A streptococcal infection.
Recurrent group A Streptococcus (GAS) tonsillitis and associated autoimmune diseases indicate that the immune response to this organism can be ineffective and pathological. TGF-beta1 is recognized as an essential signal for generation of regulatory T cells (Tregs) and T helper (Th) 17 cells. Here, the impact of TGF-beta1 induction on the T-cell response in mouse nasal-associated lymphoid tissue (NALT) following intranasal (i.n.) infections is investigated. ELISA and TGF-beta1-luciferase reporter assays indicated that persistent infection of mouse NALT with GAS sets the stage for TGF-beta1 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-beta1 signaling-dependent manner in single-cell suspensions of both human tonsils and NALT. Intracellular cytokine staining and flow cytometry demonstrated that CD4(+) IL-17(+) T cells are the dominant T cells induced in NALT by i.n. infections. Moreover, naive mice acquired the potential to clear GAS by adoptive transfer of CD4(+) T cells from immunized IL-17A(+)/(+) mice but not cells from IL-17A(-)/(-) mice. These experiments link specific induction of TGF-beta1 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.
Wang
Beinan
B
Department of Microbiology, and Discovery Genomics, Inc, Minneapolis, MN 55413, USA. wangx351@umn.edu
Dileepan
Thamotharampillai
T
Briscoe
Sarah
S
Hyland
Kendra A
KA
Kang
Johnthomas
J
Khoruts
Alexander
A
Cleary
P Patrick
PP
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000276:immunology / Q000472:pathogenicity; D008088:Listeriosis / Q000276:immunology / Q000473:pathology; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009296:Nasal Cavity / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D013290:Streptococcal Infections / Q000276:immunology* / Q000473:pathology*; D013297:Streptococcus pyogenes / Q000276:immunology / Q000472:pathogenicity; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology*; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D014069:Tonsillitis / Q000276:immunology / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*
D016207:Cytokines; D020381:Interleukin-17; D053773:Transforming Growth Factor beta1