Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor.
CD4(+) helper T (Th) cells differentiate toward distinct effector cell lineages characterized by their distinct cytokine expression patterns and functions. Multiple Th cell populations secrete IL-22 that contributes to both protective and pathological inflammatory responses. Although the differentiation of IL-22-producing Th cells is controlled by the aryl hydrocarbon receptor (AhR), little is known about the regulatory mechanisms inducing physiological stimulators for AhR. Here, we show that Notch signaling enhances IL-22 production by CD4(+) T cells by a mechanism involving AhR stimulation. Notch-mediated stimulation of CD4(+) T cells increased the production of IL-22 even in the absence of STAT3. CD4(+) T cells from RBP-J-deficient mice had little ability to produce IL-22 through T cell receptor-mediated stimulation. RBP-J-deficient mice were highly susceptible to the detrimental immunopathology associated with ConA-induced hepatitis with little IL-22 production by CD4(+) T cells. Exogenous IL-22 protected RBP-J-deficient mice from ConA-induced hepatitis. Notch signaling promoted production of endogenous stimulators for AhR, which further augmented IL-22 secretion. Our studies identify a Notch-AhR axis that regulates IL-22 expression and fine-tunes immune system control of inflammatory responses.
Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan.
Muhammad Shamsul
MS
Alam
Yoichi
Y
Maekawa
Akiko
A
Kitamura
Kenji
K
Tanigaki
Takayuki
T
Yoshimoto
Kenji
K
Kishihara
Koji
K
Yasutomo
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D005260:Female; D006520:Hepatitis, Animal / Q000209:etiology / Q000276:immunology; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D051880:Receptors, Notch / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D000097043:Interleukin-22
D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007378:Interleukins; D018336:Receptors, Aryl Hydrocarbon; D051880:Receptors, Notch; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C497571:Rbpj protein, mouse; C494087:Stat3 protein, mouse