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Biased chemokine responses

Like many other G protein–coupled receptors (GPCRs), chemokine receptors exhibit so-called biased agonism, whereby different ligands can stimulate either G protein– or β-arrestin–dependent signaling. Smith et al. investigated biased signaling by the receptor CXCR3, which directs T cell migration to sites of inflammation. The authors found that topical application of a small-molecule agonist that was β-arrestin biased, but not one that was G protein biased, exacerbated inflammation in a mouse model of contact hypersensitivity. The β-arrestin–biased agonist was more potent at stimulating mouse and human T cell chemotaxis in vitro and activated the kinase Akt, which promoted migration. Together, these data suggest that biased agonists of CXCR3, and perhaps other chemokine receptors, result in different physiological outcomes.

Abstract

The chemokine receptor CXCR3 plays a central role in inflammation by mediating effector/memory T cell migration in various diseases; however, drugs targeting CXCR3 and other chemokine receptors are largely ineffective in treating inflammation. Chemokines, the endogenous peptide ligands of chemokine receptors, can exhibit so-called biased agonism by selectively activating either G protein– or β-arrestin–mediated signaling after receptor binding. Biased agonists might be used as more targeted therapeutics to differentially regulate physiological responses, such as immune cell migration. To test whether CXCR3-mediated physiological responses could be segregated by G protein– and β-arrestin–mediated signaling, we identified and characterized small-molecule biased agonists of the receptor. In a mouse model of T cell–mediated allergic contact hypersensitivity (CHS), topical application of a β-arrestin–biased, but not a G protein–biased, agonist potentiated inflammation. T cell recruitment was increased by the β-arrestin–biased agonist, and biopsies of patients with allergic CHS demonstrated coexpression of CXCR3 and β-arrestin in T cells. In mouse and human T cells, the β-arrestin–biased agonist was the most efficient at stimulating chemotaxis. Analysis of phosphorylated proteins in human lymphocytes showed that β-arrestin–biased signaling activated the kinase Akt, which promoted T cell migration. This study demonstrates that biased agonists of CXCR3 produce distinct physiological effects, suggesting discrete roles for different endogenous CXCR3 ligands and providing evidence that biased signaling can affect the clinical utility of drugs targeting CXCR3 and other chemokine receptors.
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Supplementary Material

Summary

Fig. S1. Additional signaling analyses of CXCR3 ligands.
Fig. S2. Biased signaling is conserved at murine CXCR3.
Fig. S3. The inflammatory effects of the β-arrestin–biased agonist VUF10661 are absent in CXCR3 KO mice.
Fig. S4. Loss of β-arrestin2 attenuates chemotaxis to mCXCL10, and both VUF10661 and mCXCL10 induce chemotaxis of only CD44+ T cell populations.
Fig. S5. Biased ligands of CXCR3 differentially increased the numbers of CD4+CD44+ T cells and total T cells in DNFB-treated ears.
Fig. S6. Human T cell chemotaxis.
Fig. S7. Targeted phosphoprotein data in T cells, monocytes, and natural killer cells.
Fig. S8. Co-immunoprecipitation of pAkt-Thr308 with β-arrestin2.
Fig. S9. Differential phosphorylation of Akt, but not ERK1/2, in a T cell line stably expressing CXCR3 after stimulation with VUF10661 or VUF11418.
Fig. S10. Both PTX and a PI3K inhibitor eliminate effector T cell migration to VUF10661.
Fig. S11. Flow cytometry gating strategy.
Table S1. Pharmacological properties of the biased agonists of CXCR3.
Table S2. Flow cytometry antibodies.

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REFERENCES AND NOTES

1
T. J. Schall, A. E. I. Proudfoot, Overcoming hurdles in developing successful drugs targeting chemokine receptors. Nat. Rev. Immunol. 11, 355–363 (2011).
2
J. R. Groom, A. D. Luster, CXCR3 ligands: Redundant, collaborative and antagonistic functions. Immunol. Cell Biol. 89, 207–215 (2011).
3
M. Ogura, T. Ishida, K. Hatake, M. Taniwaki, K. Ando, K. Tobinai, K. Fujimoto, K. Yamamoto, T. Miyamoto, N. Uike, M. Tanimoto, K. Tsukasaki, K. Ishizawa, J. Suzumiya, H. Inagaki, K. Tamura, S. Akinaga, M. Tomonaga, R. Ueda, Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-CC chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J. Clin. Oncol. 32, 1157–1163 (2014).
4
R. Santos, O. Ursu, A. Gaulton, A. P. Bento, R. S. Donadi, C. G. Bologa, A. Karlsson, B. Al-Lazikani, A. Hersey, T. I. Oprea, J. P. Overington, A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16, 19–34 (2017).
5
A. Mantovani, The chemokine system: Redundancy for robust outputs. Immunol. Today 20, 254–257 (1999).
6
E. G. Strungs, L. M. Luttrell, Arrestin-dependent activation of ERK and Src family kinases. Handb. Exp. Pharmacol. 219, 225–257 (2014).
7
L. J. Drury, J. J. Ziarek, S. Gravel, C. T. Veldkamp, T. Takekoshi, S. T. Hwang, N. Heveker, B. F. Volkman, M. B. Dwinell, Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways. Proc. Natl. Acad. Sci. U.S.A. 108, 17655–17660 (2011).
8
S. Rajagopal, D. L. Bassoni, J. J. Campbell, N. P. Gerard, C. Gerard, T. S. Wehrman, Biased agonism as a mechanism for differential signaling by chemokine receptors. J. Biol. Chem. 288, 35039–35048 (2013).
9
D. A. Zidar, J. D. Violin, E. J. Whalen, R. J. Lefkowitz, Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands. Proc. Natl. Acad. Sci. U.S.A. 106, 9649–9654 (2009).
10
J. D. Urban, W. P. Clarke, M. von Zastrow, D. E. Nichols, B. Kobilka, H. Weinstein, J. A. Javitch, B. L. Roth, A. Christopoulos, P. M. Sexton, K. J. Miller, M. Spedding, R. B. Mailman, Functional selectivity and classical concepts of quantitative pharmacology. J. Pharmacol. Exp. Ther. 320, 1–13 (2007).
11
J. S. Smith, S. Rajagopal, The β-arrestins: Multifunctional regulators of G protein-coupled receptors. J. Biol. Chem. 291, 8969–8977 (2016).
12
D. G. Soergel, R. A. Subach, N. Burnham, M. W. Lark, I. E. James, B. M. Sadler, F. Skobieranda, J. D. Violin, L. R. Webster, Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers. Pain 155, 1829–1835 (2014).
13
A. Manglik, H. Lin, D. K. Aryal, J. D. McCorvy, D. Dengler, G. Corder, A. Levit, R. C. Kling, V. Bernat, H. Hübner, X.-P. Huang, M. F. Sassano, P. M. Giguère, S. Löber, D. Da, G. Scherrer, B. K. Kobilka, P. Gmeiner, B. L. Roth, B. K. Shoichet, Structure-based discovery of opioid analgesics with reduced side effects. Nature 537, 185–190 (2016).
14
T. F. Brust, J. Morgenweck, S. A. Kim, J. H. Rose, J. L. Locke, C. L. Schmid, L. Zhou, E. L. Stahl, M. D. Cameron, S. M. Scarry, J. Aubé, S. R. Jones, T. J. Martin, L. M. Bohn, Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Sci. Signal. 9, ra117 (2016).
15
M. M. Monasky, D. M. Taglieri, M. Henze, C. M. Warren, M. S. Utter, D. G. Soergel, J. D. Violin, R. J. Solaro, The β-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium. Am. J. Physiol. Heart Circ. Physiol. 305, H856–H866 (2013).
16
J. S. Smith, R. J. Lefkowitz, S. Rajagopal, Biased signalling: From simple switches to allosteric microprocessors. Nat. Rev. Drug Discov. 17, 243–260 (2018).
17
C. L. Schmid, N. M. Kennedy, N. C. Ross, K. M. Lovell, Z. Yue, J. Morgenweck, M. D. Cameron, T. D. Bannister, L. M. Bohn, Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell 171, 1165–1175.e13 (2017).
18
J. G. Cyster, C. C. Goodnow, Pertussis toxin inhibits migration of B and T lymphocytes into splenic white pulp cords. J. Exp. Med. 182, 581–586 (1995).
19
M. Thelen, Dancing to the tune of chemokines. Nat. Immunol. 2, 129–134 (2001).
20
T. A. Kohout, S. L. Nicholas, S. J. Perry, G. Reinhart, S. Junger, R. S. Struthers, Differential desensitization, receptor phosphorylation, β-arrestin recruitment, and ERK1/2 activation by the two endogenous ligands for the CC chemokine receptor 7. J. Biol. Chem. 279, 23214–23222 (2004).
21
M. J. Orsini, J.-L. Parent, S. J. Mundell, A. Marchese, J. L. Benovic, Trafficking of the HIV coreceptor CXCR4. Role of arrestins and identification of residues in the C-terminal tail that mediate receptor internalization. J. Biol. Chem. 274, 31076–31086 (1999).
22
I. Aramori, S. S. G. Ferguson, P. D. Bieniasz, J. Zhang, B. R. Cullen, M. G. Cullen, Molecular mechanism of desensitization of the chemokine receptor CCR-5: Receptor signaling and internalization are dissociable from its role as an HIV-1 co-receptor. EMBO J. 16, 4606–4616 (1997).
23
A. M. Fong, R. T. Premont, R. M. Richardson, Y.-R. A. Yu, R. J. Lefkowitz, D. D. Patel, Defective lymphocyte chemotaxis in β-arrestin2- and GRK6-deficient mice. Proc. Natl. Acad. Sci. U.S.A. 99, 7478–7483 (2002).
24
J. D. Wolchok, V. Chiarion-Sileni, R. Gonzalez, P. Rutkowski, J.-J. Grob, C. L. Cowey, C. D. Lao, J. Wagstaff, D. Schadendorf, P. F. Ferrucci, M. Smylie, R. Dummer, A. Hill, D. Hogg, J. Haanen, M. S. Carlino, O. Bechter, M. Maio, I. Marquez-Rodas, M. Guidoboni, G. McArthur, C. Lebbé, P. A. Ascierto, G. V. Long, J. Cebon, J. Sosman, M. A. Postow, M. K. Callahan, D. Walker, L. Rollin, R. Bhore, F. S. Hodi, J. Larkin, Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).
25
E. J. A. van Wanrooij, S. C. A. de Jager, T. van Es, P. de Vos, H. L. Birch, D. A. Owen, R. J. Watson, E. A. L. Biessen, G. A. Chapman, T. J. C. van Berkel, J. Kuiper, CXCR3 antagonist NBI-74330 attenuates atherosclerotic plaque formation in LDL receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 28, 251–257 (2008).
26
M. Rashighi, P. Agarwal, J. M. Richmond, T. H. Harris, K. Dresser, M.-W. Su, Y. Zhou, A. Deng, C. A. Hunter, A. D. Luster, J. E. Harris, CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci. Transl. Med. 6, 223ra23 (2014).
27
J. M. Richmond, E. Masterjohn, R. Chu, J. Tedstone, M. E. Youd, J. E. Harris, CXCR3 depleting antibodies prevent and reverse vitiligo in mice. J. Invest. Dermatol. 137, 982–985 (2017).
28
J. Flier, D. M. Boorsma, D. P. Bruynzeel, P. J. Van Beek, T. J. Stoof, R. J. Scheper, R. Willemze, C. P. Tensen, The CXCR3 activating chemokines IP-10, Mig, and IP-9 are expressed in allergic but not in irritant patch test reactions. J. Invest. Dermatol. 113, 574–578 (1999).
29
R. A. Colvin, G. S. V. Campanella, J. Sun, A. D. Luster, Intracellular domains of CXCR3 that mediate CXCL9, CXCL10, and CXCL11 function. J. Biol. Chem. 279, 30219–30227 (2004).
30
J. S. Smith, P. Alagesan, N. K. Desai, T. F. Pack, J.-H. Wu, A. Inoue, N. J. Freedman, S. Rajagopal, C-X-C motif chemokine receptor 3 splice variants differentially activate β-arrestins to regulate downstream signaling pathways. Mol. Pharmacol. 92, 136–150 (2017).
31
I. L. Stroke, A. G. Cole, S. Simhadri, M.-R. Brescia, M. Desai, J. J. Zhang, J. R. Merritt, K. C. Appell, I. Henderson, M. L. Webb, Identification of CXCR3 receptor agonists in combinatorial small-molecule libraries. Biochem. Biophys. Res. Commun. 349, 221–228 (2006).
32
D. J. Scholten, M. Wijtmans, J. R. van Senten, H. Custers, A. Stunnenberg, I. J. P. de Esch, M. J. Smit, R. Leurs, Pharmacological characterization of [3H]VUF11211, a novel radiolabeled small-molecule inverse agonist for the chemokine receptor CXCR3. Mol. Pharmacol. 87, 639–648 (2015).
33
M. Wijtmans, D. J. Scholten, L. Roumen, M. Canals, H. Custers, M. Glas, M. C. A. Vreeker, F. J. J. de Kanter, C. de Graaf, M. J. Smit, I. J. P. de Esch, R. Leurs, Chemical subtleties in small-molecule modulation of peptide receptor function: The case of CXCR3 biaryl-type ligands. J. Med. Chem. 55, 10572–10583 (2012).
34
D. J. Scholten, M. Canals, M. Wijtmans, S. de Munnik, P. Nguyen, D. Verzijl, I. J. P. de Esch, H. F. Vischer, M. J. Smit, R. Leurs, Pharmacological characterization of a small-molecule agonist for the chemokine receptor CXCR3. Br. J. Pharmacol. 166, 898–911 (2012).
35
Y. A. Berchiche, T. P. Sakmar, CXC chemokine receptor 3 alternative splice variants selectively activate different signaling pathways. Mol. Pharmacol. 90, 483–495 (2016).
36
S. Sebastiani, C. Albanesi, F. Nasorri, G. Girolomoni, A. Cavani, Nickel-specific CD4+ and CD8+ T cells display distinct migratory responses to chemokines produced during allergic contact dermatitis. J. Invest. Dermatol. 118, 1052–1058 (2002).
37
R. Cheung, M. Malik, V. Ravyn, B. Tomkowicz, A. Ptasznik, R. G. Collman, An arrestin-dependent multi-kinase signaling complex mediates MIP-1β/CCL4 signaling and chemotaxis of primary human macrophages. J. Leukoc. Biol. 86, 833–845 (2009).
38
K. A. DeFea, Stop that cell! β-Arrestin-dependent chemotaxis: A tale of localized actin assembly and receptor desensitization. Annu. Rev. Physiol. 69, 535–560 (2007).
39
R. Solari, J. E. Pease, M. Begg, Chemokine receptors as therapeutic targets: Why aren’t there more drugs? Eur. J. Pharmacol. 746, 363–367 (2015).
40
A. Cavani, D. Mei, E. Guerra, S. Corinti, M. Giani, L. Pirrotta, P. Puddu, G. Girolomoni, Patients with allergic contact dermatitis to nickel and nonallergic individuals display different nickel-specific T cell responses. Evidence for the presence of effector CD8+ and regulatory CD4+ T cells. J. Invest. Dermatol. 111, 621–628 (1998).
41
A. Tohgo, E. W. Choy, D. Gesty-Palmer, K. L. Pierce, S. Laporte, R. H. Oakley, M. G. Caron, R. J. Lefkowitz, L. M. Luttrell, The stability of the G protein-coupled receptor-β-arrestin interaction determines the mechanism and functional consequence of ERK activation. J. Biol. Chem. 278, 6258–6267 (2003).
42
S. Ahn, S. K. Shenoy, H. Wei, R. J. Lefkowitz, Differential kinetic and spatial patterns of β-arrestin and G protein-mediated ERK activation by the angiotensin II receptor. J. Biol. Chem. 279, 35518–35525 (2004).
43
H. L. Nichols, M. Saffeddine, B. S. Theriot, A. Hegde, D. Polley, T. El-Mays, H. Vliagoftis, M. D. Hollenberg, E. H. Wilson, J. K. L. Walker, K. A. DeFea, β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway. Proc. Natl. Acad. Sci. U.S.A. 109, 16660–16665 (2012).
44
M. Zoudilova, J. Min, H. L. Richards, D. Carter, T. Huang, K. A. DeFea, β-Arrestins scaffold cofilin with chronophin to direct localized actin filament severing and membrane protrusions downstream of protease-activated receptor-2. J. Biol. Chem. 285, 14318–14329 (2010).
45
L. Ge, Y. Ly, M. Hollenberg, K. DeFea, A β-arrestin-dependent scaffold is associated with prolonged MAPK activation in pseudopodia during protease-activated receptor-2-induced chemotaxis. J. Biol. Chem. 278, 34418–34426 (2003).
46
D. L. Hunton, W. G. Barnes, J. Kim, X.-R. Ren, J. D. Violin, E. Reiter, G. Milligan, D. D. Patel, R. J. Lefkowitz, β-Arrestin 2-dependent angiotensin II type 1A receptor-mediated pathway of chemotaxis. Mol. Pharmacol. 67, 1229–1236 (2005).
47
R. Meili, C. Ellsworth, S. Lee, T. B. K. Reddy, H. Ma, R. A. Firtel, Chemoattractant-mediated transient activation and membrane localization of Akt/PKB is required for efficient chemotaxis to cAMP in Dictyostelium. EMBO J. 18, 2092–2105 (1999).
48
M. Morales-Ruiz, M.-J. Lee, S. Zöllner, J.-P. Gratton, R. Scotland, I. Shiojima, K. Walsh, T. Hla, W. C. Sessa, Sphingosine 1-phosphate activates Akt, nitric oxide production, and chemotaxis through a Gi protein/phosphoinositide 3-kinase pathway in endothelial cells. J. Biol. Chem. 276, 19672–19677 (2001).
49
Y. Zohar, G. Wildbaum, R. Novak, A. L. Salzman, M. Thelen, R. Alon, Y. Barsheshet, C. L. Karp, N. Karin, CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis. J. Clin. Invest. 124, 2009–2022 (2014).
50
A. Bonacchi, P. Romagnani, R. G. Romanelli, E. Efsen, F. Annunziato, L. Lasagni, M. Francalanci, M. Serio, G. Laffi, M. Pinzani, P. Gentilini, F. Marra, Signal transduction by the chemokine receptor CXCR3: Activation of Ras/ERK, Src, and phosphatidylinositol 3-kinase/Akt controls cell migration and proliferation in human vascular pericytes. J. Biol. Chem. 276, 9945–9954 (2001).
51
J.-M. Beaulieu, T. D. Sotnikova, S. Marion, R. J. Lefkowitz, R. R. Gainetdinov, M. G. Caron, An Akt/β-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122, 261–273 (2005).
52
J.-M. Beaulieu, S. Marion, R. M. Rodriguiz, I. O. Medvedev, T. D. Sotnikova, V. Ghisi, W. C. Wetsel, R. J. Lefkowitz, R. R. Gainetdinov, M. G. Caron, A β-arrestin 2 signaling complex mediates lithium action on behavior. Cell 132, 125–136 (2008).
53
B. Luan, J. Zhao, H. Wu, B. Duan, G. Shu, X. Wang, D. Li, W. Jia, J. Kang, G. Pei, Deficiency of a β-arrestin-2 signal complex contributes to insulin resistance. Nature 457, 1146–1149 (2009).
54
B. Lagane, K. Y. C. Chow, K. Balabanian, A. Levoye, J. Harriague, T. Planchenault, F. Baleux, N. Gunera-Saad, F. Arenzana-Seisdedos, F. Bachelerie, CXCR4 dimerization and β-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome. Blood 112, 34–44 (2008).
55
J. Quoyer, J. M. Janz, J. Luo, Y. Ren, S. Armando, V. Lukashova, J. L. Benovic, K. E. Carlson, S. W. Hunt III, M. Bouvier, Pepducin targeting the C-X-C chemokine receptor type 4 acts as a biased agonist favoring activation of the inhibitory G protein. Proc. Natl. Acad. Sci. U.S.A. 110, E5088–E5097 (2013).
56
M. D. Gunn, K. Tangemann, C. Tam, J. G. Cyster, S. D. Rosen, L. T. Williams, A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc. Natl. Acad. Sci. U.S.A. 95, 258–263 (1998).
57
M. A. Cox, C.-H. Jenh, W. Gonsiorek, J. Fine, S. K. Narula, P. J. Zavodny, R. W. Hipkin, Human interferon-inducible 10-kDa protein and human interferon-inducible T cell α chemoattractant are allotopic ligands for human CXCR3: Differential binding to receptor states. Mol. Pharmacol. 59, 707–715 (2001).
58
A. B. Kleist, A. E. Getschman, J. J. Ziarek, A. M. Nevins, P.-A. Gauthier, A. Chevigné, M. Szpakowska, B. F. Volkman, New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model. Biochem. Pharmacol. 114, 53–68 (2016).
59
R. A. Colvin, G. S. V. Campanella, L. A. Manice, A. D. Luster, CXCR3 requires tyrosine sulfation for ligand binding and a second extracellular loop arginine residue for ligand-induced chemotaxis. Mol. Cell. Biol. 26, 5838–5849 (2006).
60
P. G. Charest, S. Terrillon, M. Bouvier, Monitoring agonist-promoted conformational changes of β-arrestin in living cells by intramolecular BRET. EMBO Rep. 6, 334–340 (2005).
61
S. Angers, A. Salahpour, E. Joly, S. Hilairet, D. Chelsky, M. Dennis, M. Bouvier, Detection of β2-adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET). Proc. Natl. Acad. Sci. U.S.A. 97, 3684–3689 (2000).
62
A. Inoue, J. Ishiguro, H. Kitamura, N. Arima, M. Okutani, A. Shuto, S. Higashiyama, T. Ohwada, H. Arai, K. Makide, J. Aoki, TGFα shedding assay: An accurate and versatile method for detecting GPCR activation. Nat. Methods 9, 1021–1029 (2012).
63
B. D. Thompson, Y. Jin, K. H. Wu, R. A. Colvin, A. D. Luster, L. Birnbaumer, M. X. Wu, Inhibition of Gαi2 activation by Gαi3 in CXCR3-mediated signaling. J. Biol. Chem. 282, 9547–9555 (2007).
64
M. T. Drake, J. D. Violin, E. J. Whalen, J. W. Wisler, S. K. Shenoy, R. J. Lefkowitz, β-Arrestin-biased agonism at the β2-adrenergic receptor. J. Biol. Chem. 283, 5669–5676 (2008).
65
J. Suwanpradid, M. Shih, L. Pontius, B. Yang, A. Birukova, E. Guttman-Yassky, D. L. Corcoran, L. G. Que, R. M. Tighe, A. S. MacLeod, Arginase1 deficiency in monocytes/macrophages upregulates inducible nitric oxide synthase to promote cutaneous contact hypersensitivity. J. Immunol. 199, 1827–1834 (2017).
66
I. Moraga, G. Wernig, S. Wilmes, V. Gryshkova, C. P. Richter, W.-J. Hong, R. Sinha, F. Guo, H. Fabionar, T. S. Wehrman, P. Krutzik, S. Demharter, I. Plo, I. L. Weissman, P. Minary, R. Majeti, S. N. Constantinescu, J. Piehler, K. C. Garcia, Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands. Cell 160, 1196–1208 (2015).

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Science Signaling
Volume 11 | Issue 555
November 2018

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Received: 2 October 2017
Accepted: 19 October 2018

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Acknowledgments

We thank R. J. Lefkowitz (Duke University, USA) for guidance, mentorship, and thoughtful feedback throughout this work and for supplying C57BL/6 ARRB2−/− mice; R. Premont (Harrington Discovery Institute, USA) for providing the GRK-YFP constructs; A. Inoue (Tohoku University, Japan) for G protein KO cells; M. Caron, S. Shenoy, and N. Freedman for the use of laboratory equipment; T. Pack, A. Wisdom, and M.-N. Huang for many helpful discussions; N. Nazo for laboratory assistance; and K. Hines and K. Scoggins for assistance in patient sample acquisition. Funding: This work was supported by T32GM7171 (J.S.S.), the Duke Medical Scientist Training Program (J.S.S.), 1R01GM122798-01A1 (S.R.), K08HL114643-01A1, (S.R.), Burroughs Wellcome Career Award for Medical Scientists (S.R.), R21AI28727 (A.S.M.), R01AI39207 (A.S.M.), Duke Physician-Scientist Strong Start Award (A.S.M.), Dermatology Foundation Research Grant (A.S.M.), and the Duke Pinnell Center for Investigative Dermatology (J.S.S., A.S.M., and S.R.). Author contributions: J.S.S. and S.R. conceived and planned the study. J.S.S., L.T.N., T.S.W., A.R.A., M.D.G., A.S.M., and S.R. helped plan and review experiments. J.S.S., L.T.N., J.S., R.A.G, N.M.K., P.A., J.N.G., T.S.W., and A.S.M. performed experiments. J.S.S., L.T.N., and S.R. analyzed flow cytometry data. A.S.M. and J.S. performed and analyzed immunohistochemistry data. J.S.S. and S.R. analyzed all other data. J.S.S. and S.R. wrote the paper. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

Authors

Affiliations

Department of Biochemistry, Duke University, Durham, NC 27710, USA.
Department of Medicine, Duke University, Durham, NC 27710, USA.
Lowell T. Nicholson
Department of Medicine, Duke University, Durham, NC 27710, USA.
Jutamas Suwanpradid
Department of Dermatology, Duke University, Durham, NC 27710, USA.
Rachel A. Glenn
Department of Biochemistry, Duke University, Durham, NC 27710, USA.
Department of Biochemistry, Duke University, Durham, NC 27710, USA.
Department of Biochemistry, Duke University, Durham, NC 27710, USA.
Jaimee N. Gundry
Department of Biochemistry, Duke University, Durham, NC 27710, USA.
Thomas S. Wehrman
Primity Bio, Fremont, CA 94538, USA.
Amber Reck Atwater
Department of Dermatology, Duke University, Durham, NC 27710, USA.
Department of Medicine, Duke University, Durham, NC 27710, USA.
Department of Immunology, Duke University, Durham, NC 27710, USA.
Amanda S. MacLeod
Department of Dermatology, Duke University, Durham, NC 27710, USA.
Department of Immunology, Duke University, Durham, NC 27710, USA.
Department of Biochemistry, Duke University, Durham, NC 27710, USA.
Department of Medicine, Duke University, Durham, NC 27710, USA.

Funding Information

Duke Pinnell Center for Investigative Dermatology:
Duke Physician-Scientist Strong Start Award:
Dermatology Foundation Research Grant:
Duke Medical Scientist Training Program:

Notes

*Corresponding author. Email: sudarshan.rajagop[email protected]

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