Signaling through the adaptor molecule MyD88 in CD4+ T cells is required to overcome suppression by regulatory T cells.
Innate immune recognition controls adaptive immune responses through multiple mechanisms. The MyD88 signaling adaptor operates in many cell types downstream of Toll-like receptors (TLRs) and interleukin-1 (IL-1) receptor family members. Cell-type-specific functions of MyD88 signaling remain poorly characterized. Here, we have shown that the T cell-specific ablation of MyD88 in mice impairs not only T helper 17 (Th17) cell responses, but also Th1 cell responses. MyD88 relayed signals of TLR-induced IL-1, which became dispensable for Th1 cell responses in the absence of T regulatory (Treg) cells. Treg cell-specific ablation of MyD88 had no effect, suggesting that IL-1 acts on naive CD4(+) T cells instead of Treg cells themselves. Together, these findings demonstrate that IL-1 renders naive CD4(+) T cells refractory to Treg cell-mediated suppression in order to allow their differentiation into Th1 cells. In addition, IL-1 was also important for the generation of functional CD4(+) memory T cells.
Department of Immunobiology, Yale University, New Haven, CT 06519, USA; Howard Hughes Medical Institute, School of Medicine, Yale University, New Haven, CT 06519, USA. Electronic address: dominik.schenten@yale.edu.
Dominik
D
Schenten
Department of Immunobiology, Yale University, New Haven, CT 06519, USA; Howard Hughes Medical Institute, School of Medicine, Yale University, New Haven, CT 06519, USA.
Simone A
SA
Nish
Department of Immunobiology, Yale University, New Haven, CT 06519, USA; Howard Hughes Medical Institute, School of Medicine, Yale University, New Haven, CT 06519, USA.
Shuang
S
Yu
Department of Biostatistics, Yale School of Public Health, New Haven, CT 06520, USA.
Xiting
X
Yan
Department of Immunobiology, Yale University, New Haven, CT 06519, USA; Howard Hughes Medical Institute, School of Medicine, Yale University, New Haven, CT 06519, USA.
Heung Kyu
HK
Lee
Department of Immunobiology, Yale University, New Haven, CT 06519, USA; Howard Hughes Medical Institute, School of Medicine, Yale University, New Haven, CT 06519, USA.
Igor
I
Brodsky
Department of Immunobiology, Yale University, New Haven, CT 06519, USA; Howard Hughes Medical Institute, School of Medicine, Yale University, New Haven, CT 06519, USA.
Lesley
L
Pasman
Department of Immunobiology, Yale University, New Haven, CT 06519, USA.
Brian
B
Yordy
Max Planck Institute for Neurological Research, Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), Institute for Genetics, University of Cologne, 50931 Cologne, Germany.
F Thomas
FT
Wunderlich
Max Planck Institute for Neurological Research, Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), Institute for Genetics, University of Cologne, 50931 Cologne, Germany.
Jens C
JC
Brüning
Department of Biostatistics, Yale School of Public Health, New Haven, CT 06520, USA.
Hongyu
H
Zhao
Department of Immunobiology, Yale University, New Haven, CT 06519, USA; Howard Hughes Medical Institute, School of Medicine, Yale University, New Haven, CT 06519, USA. Electronic address: ruslan.medzhitov@yale.edu.
Ruslan
R
Medzhitov
D056704:Adaptive Immunity; D000818:Animals; D002478:Cells, Cultured; D007113:Immunity, Innate; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D007375:Interleukin-1 / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
D007375:Interleukin-1; D020382:Interleukin-18; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1