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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02641

Defining the signature of VISTA on myeloid cell chemokine responsiveness

 Thomas Broughton1,  Mohamed ElTanbouly1,  Evelien Schaafsma1, Jie Deng1,  Aurelien Sarde1, Walburga Croteau1,  Jiannan Li1, Elizabeth Nowak1,  Rodwell Mabaera2,  Nicole Smits1, Anna Kuta3, Randolph Noelle1* and  J. L. Lines1*
  • 1Dartmouth College, United States
  • 2Dartmouth–Hitchcock Medical Center, United States
  • 3ImmuNext (United States), United States

The role of negative checkpoint regulators (NCRs) in human health and disease cannot be overstated. V-domain Ig-containing Suppressor of T-cell Activation (VISTA) is an Ig superfamily protein predominantly expressed within the hematopoietic compartment and has been studied for its role in the negative regulation of T cell responses. The findings presented in this study show that, unlike all other NCRs, VISTA deficiency dramatically impacts on macrophage cytokine and chemokine production, as well as the chemotactic response of VISTA-deficient macrophages. A select group of inflammatory chemokines, including CCL2, CCL3, CCL4 and CCL5, was strikingly elevated in culture supernatants from VISTA KO macrophages. VISTA deficiency also altered chemokine receptor recycling and profoundly disrupted myeloid chemotaxis. The impact of VISTA deficiency on chemotaxis in vivo was apparent with the reduced ability of both KO macrophages and MDSCs to migrate to the tumor microenvironment. This is the first demonstration of an NCR impacting on myeloid mediator production and chemotaxis and will guide the use of anti-VISTA therapeutics to manipulate the chemotaxis of inflammatory macrophages or immunosuppressive MDSCs in inflammatory diseases and cancer.

Keywords: Vista, macrophage, Immune checkpoint, chemokine, Migration

Received: 21 Jun 2019; Accepted: 24 Oct 2019.

Copyright: © 2019 Broughton, ElTanbouly, Schaafsma, Deng, Sarde, Croteau, Li, Nowak, Mabaera, Smits, Kuta, Noelle and Lines. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Mx. Randolph Noelle, Dartmouth College, Hanover, 03755, Indiana, United States, Randolph.J.Noelle@dartmouth.edu
Mx. J. L. Lines, Dartmouth College, Hanover, 03755, Indiana, United States, Janet.L.Lines@dartmouth.edu