1. A Yin and Yang in Epithelial Immunology: The Roles of the αE(CD103)β7 Integrin in T Cells 
Jan-Hendrik B. Hardenberg, Andrea Braun, Michael P. Schön 
Journal of Investigative Dermatology 
Volume 138, Issue 1, Pages (January 2018)
DOI: /j.jid
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2. Figure 1
Structure and putative functions of the αE(CD103)β7 integrin. (a) Domain structure of the αE(CD103)β7 integrin. The propeller, calf, and thigh domains of the αE(CD103) chain are shared with all known integrin α-subunits, whereas the α-I-domain is found in eight others. The X-domain containing a proteolytic cleavage site is unique to αE(CD103). Intracellular signaling is primarily dependent on the tail domain of the β7-chain, which also contains four EGF-like domains, two so-called hybrid domains separated by the β-I-domain, and a plexin/semaphorin/integrin domain. (b) Involvement of αE(CD103)β7 in selected intra- and extracellular signaling events. Binding of TGF-β to a type II receptor recruits and phosphorylates a type I receptor, which then recruits and phosphorylates Smad2 or Smad3. The latter dissociate from the receptor and oligomerize with Smad4. The oligomer translocates to the nucleus, recruits regulatory factors (DNA-binding factor, p300/CBP coactivator) and initiates target gene transcription. Concomitant TCR signaling and NFAT translocation to the nucleus is essential. On TCR stimulation, PLCγ1 is activated generating IP3, which induces calcium release, thus activating the NFAT pathway. The ITGAE gene (encoding for the αE(CD103) subunit) possesses enhancer elements binding NFAT and Smad3. Runx3-expressing cells increase expression of αE(CD103)β7 on exposure to TGF-β. The FoxP3 encoding gene also contains NFAT and Smad3 binding sites, thus providing a plausible explanation for the concomitant regulation of αE(CD103)β7 and FoxP3 by TGF-β. TGF-β receptor signaling can also activate ILK that in turn changes the conformation of αE(CD103)β7 and increases its affinity to E-cadherin. Chemokine receptor signaling can also increase the E-cadherin-directed affinity of αE(CD103)β7, and ligand binding by αE(CD103)β7 facilitates cytoskeleton rearrangement and promotes cell motility. The dashed lines indicate that underlying molecular mechanisms are largely unknown or hypothetical. (c) Putative role of the αE(CD103)β7 integrin at the immunological synapse. In the absence of LFA-1/ICAM-1, αE(CD103)β7 facilitates pSMAC formation after binding to its ligand, E-cadherin. The αE(CD103)β7/E-cadherin interaction can lead to clustering of CCR5 at the immunological synapse, which allows increased responses to CCL3 secreting target cells. Furthermore, the αE(CD103)β7/E-cadherin interaction causes recruitment of cytolytic granules to the cSMAC (central SMAC) via PLCγ signaling. Exocytosis is dependent on TCR engagement. CBP, CREB (cAMP-response element binding protein)-binding protein 1; CCL, chemokine (C-C motif) ligand; CCR, C-C-motif chemokine receptor; EGF, epidermal growth factor; FoxP3, forkhead box P3; ICAM-1, intracellular adhesion molecule 1; ILK, integrin-linked kinase; IP3, inositol triphosphate; LFA-1, lymphocyte function-associated antigen; NFAT, nuclear factor of activated T cells; PLC, phospholipase; Runx3, runt-related transcription factor 3; c/pSMAC, central/peripheral supramolecular activation cluster; TCR, T-cell receptor; TGF, transforming growth factor.
Journal of Investigative Dermatology  , 23-31DOI: ( /j.jid )
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