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Review
. 2022 Jan 27;13(1):1-14.
doi: 10.4331/wjbc.v13.i1.1.

Current understanding of the role of tyrosine kinase 2 signaling in immune responses

Ryuta Muromoto  1 , Kenji Oritani  2 , Tadashi Matsuda  3
Affiliations
Review

Current understanding of the role of tyrosine kinase 2 signaling in immune responses

Ryuta Muromoto et al. World J Biol Chem. .

Abstract

Immune system is a complex network that clears pathogens, toxic substrates, and cancer cells. Distinguishing self-antigens from non-self-antigens is critical for the immune cell-mediated response against foreign antigens. The innate immune system elicits an early-phase response to various stimuli, whereas the adaptive immune response is tailored to previously encountered antigens. During immune responses, B cells differentiate into antibody-secreting cells, while naïve T cells differentiate into functionally specific effector cells [T helper 1 (Th1), Th2, Th17, and regulatory T cells]. However, enhanced or prolonged immune responses can result in autoimmune disorders, which are characterized by lymphocyte-mediated immune responses against self-antigens. Signal transduction of cytokines, which regulate the inflammatory cascades, is dependent on the members of the Janus family of protein kinases. Tyrosine kinase 2 (Tyk2) is associated with receptor subunits of immune-related cytokines, such as type I interferon, interleukin (IL)-6, IL-10, IL-12, and IL-23. Clinical studies on the therapeutic effects and the underlying mechanisms of Tyk2 inhibitors in autoimmune or chronic inflammatory diseases are currently ongoing. This review summarizes the findings of studies examining the role of Tyk2 in immune and/or inflammatory responses using Tyk2-deficient cells and mice.

Keywords: Cytokines; Immune system; Inflammation; Signal transduction; Tyrosine kinase 2.

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Conflict of interest statement

Conflict-of-interest statement: Authors declare no conflict of interests for this article.

Figures

Figure 1
Figure 1
Schematic representation of the tyrosine kinase 2-related cytokine receptors. The IL-6 receptor, which comprises IL6RA (gp80) and IL6RB (gp130) subunits, activates signal transducer and activator of transcription (STAT)1 and STAT3 through interactions with Tyrosine kinase 2 (Tyk2), Janus family of protein tyrosine kinases 1 (Jak1), and Jak2. The IL-10 receptor, which comprises IL-10R1 and IL10-R2 subunits, activates STAT1, STAT3, and STAT5 through interactions with Tyk2 and Jak1. IL-12 is a heterodimeric cytokine comprising the IL-12p35 and IL-12p40 subunits. The IL-12 receptor, which comprises IL-12Rβ1 and IL-12Rβ2, mainly activates STAT4 through interactions with Tyk2 and Jak2. The IL-12p40 component of IL-23 can dimerize with IL-23p19 to form IL-23. The IL-23 receptor, which comprises IL-12Rβ1 and IL-23R subunits, activates STAT1, STAT3, and STAT4 through interactions with Tyk2 and Jak2. The type I IFN receptor, which comprises IFNAR1 and IFNAR2 subunits, activates STAT1 and STAT2 through interactions with Tyk2 and Jak1. STAT: Signal transducer and activator of transcription; Tyk2: Tyrosine kinase 2; Jak1: Janus family of protein tyrosine kinases 1.
Figure 2
Figure 2
Schematic representation of naïve T cell differentiation into T helper 1, T helper 2, or T helper 17 cells depending on the cytokine profile. IL-12 promotes the differentiation of naïve T cells into Th1 cells. Th1 cells promote the clearance of intracellular pathogens and induce autoimmunity through the production of IFN-γ, IL-2, and TNF-α. Th1 differentiation is regulated by transcription factors such as signal transducer and activator of transcription (STAT)1, STAT4, and T-bet. IL-4 promotes the differentiation of naïve T cells into Th2 cells. Th2 cells promote the clearance of extracellular pathogens and induce allergic responses through the production of IL-4, IL-5, IL-6, and IL-13. Th2 differentiation is regulated by transcription factors such as STAT6 and GATA3. TGF-β, IL-6, and IL1 promote the differentiation of naïve T cells into Th17 cells, while IL-23 can maintain the Th17 phenotype. Th17 cells promote the clearance of extracellular pathogens and induce autoimmunity through the production of IL-17, IL-21, and IL-22. Th2 differentiation is regulated by transcription factors, such as STAT3, RORγt and RORα.
Figure 3
Figure 3
Illustration of interleukin-12 and interleukin-23, as well as their receptors and downstream signaling pathways. IL-12 and IL-23 share the p40 subunit, while their receptors share the IL-12Rβ1 subunit. The binding of IL-12 to its receptor induces the activation of Jak2 and Tyrosine kinase 2 (Tyk2), which results in signal transducer and activator of transcription (STAT)4 phosphorylation. Activated STAT4 promotes the differentiation of naïve Th cells into Th1 cells, which subsequently produce IFN-γ that is required for the development of Th1 immune response. The binding of IL-23 to its receptor induces the activation of Jak2 and Tyk2, which results in STAT3 phosphorylation. IL-23 induces the expression of IL-17A, IL-17F, and/or IL-22 and stabilizes Th17 cells. STAT: Signal transducer and activator of transcription.
Figure 4
Figure 4
Schematic representation of the involvement of tyrosine kinase 2 in immune and inflammatory responses and its pathological significance. IBD: Inflammatory bowel diseases; RA: Rheumatoid arthritis; DTH: Delayed-type hypersensitivity; HIES: Hyper IgE syndrome; EAE: Experimental autoimmune encephalomyelitis; MS: Multiple sclerosis.
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