LILRB3 (ILT5) is a myeloid cell checkpoint that elicits profound immunomodulation
LILRB3 (ILT5) is a myeloid cell checkpoint that elicits profound immunomodulation
Despite advances in identifying the key immunoregulatory roles of many of the human leukocyte immunoglobulin-like receptor (LILR) family members, the function of the inhibitory molecule LILRB3 (ILT5, CD85a, LIR3) remains unclear. Studies indicate a predominant myeloid expression; however, high homology within the LILR family and a relative paucity of reagents have hindered progress toward identifying the function of this receptor. To investigate its function and potential immunomodulatory capacity, a panel of LILRB3-specific monoclonal antibodies (mAbs) was generated. LILRB3-specific mAbs bound to discrete epitopes in Ig-like domain 2 or 4. LILRB3 ligation on primary human monocytes by an agonistic mAb resulted in phenotypic and functional changes, leading to potent inhibition of immune responses in vitro, including significant reduction in T cell proliferation. Importantly, agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells. Our findings reveal powerful immunosuppressive functions of LILRB3 and identify it as an important myeloid checkpoint receptor.
Immunology, Immunotherapy, Macrophages, Monocytes
Yeboah, Muchaala
1a3d6a64-4374-4db5-aa6f-6c9ff7542830
Papagregoriou, Charys
c7b077d1-4274-49c4-b848-f05a23350a30
Jones, Des C.
f82edca9-6a9a-43c6-9378-7d435c833bc5
Chan, Hak
b109c93f-7e9a-44ee-ad12-da757b1b11fc
Hu, Guangan
a180f467-f206-4878-b094-60ecacc834c7
McPartlan, Justine
b22c99fb-9e7f-4211-aa84-c9ad301b7cd5
Mockridge, Christopher
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Tews, Ivo
9117fc5e-d01c-4f8d-a734-5b14d3eee8dd
Glennie, Martin
9f6f0eff-4560-48c2-80cd-0ec116110ded
Thirdborough, Stephen
161784fb-c8e3-4beb-86b1-cd8bc8ddf8de
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Roghanian, Ali
e2b032c2-60a0-4522-a3d8-56a768792f36
1 September 2020
Yeboah, Muchaala
1a3d6a64-4374-4db5-aa6f-6c9ff7542830
Papagregoriou, Charys
c7b077d1-4274-49c4-b848-f05a23350a30
Jones, Des C.
f82edca9-6a9a-43c6-9378-7d435c833bc5
Chan, Hak
b109c93f-7e9a-44ee-ad12-da757b1b11fc
Hu, Guangan
a180f467-f206-4878-b094-60ecacc834c7
McPartlan, Justine
b22c99fb-9e7f-4211-aa84-c9ad301b7cd5
Mockridge, Christopher
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Tews, Ivo
9117fc5e-d01c-4f8d-a734-5b14d3eee8dd
Glennie, Martin
9f6f0eff-4560-48c2-80cd-0ec116110ded
Thirdborough, Stephen
161784fb-c8e3-4beb-86b1-cd8bc8ddf8de
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Roghanian, Ali
e2b032c2-60a0-4522-a3d8-56a768792f36
Yeboah, Muchaala, Papagregoriou, Charys, Jones, Des C., Chan, Hak, Hu, Guangan, McPartlan, Justine, Mockridge, Christopher, Tews, Ivo, Glennie, Martin, Thirdborough, Stephen, Cragg, Mark and Roghanian, Ali
(2020)
LILRB3 (ILT5) is a myeloid cell checkpoint that elicits profound immunomodulation.
JCI Insight, 5 (18), [e141593].
(doi:10.1172/jci.insight.141593).
Abstract
Despite advances in identifying the key immunoregulatory roles of many of the human leukocyte immunoglobulin-like receptor (LILR) family members, the function of the inhibitory molecule LILRB3 (ILT5, CD85a, LIR3) remains unclear. Studies indicate a predominant myeloid expression; however, high homology within the LILR family and a relative paucity of reagents have hindered progress toward identifying the function of this receptor. To investigate its function and potential immunomodulatory capacity, a panel of LILRB3-specific monoclonal antibodies (mAbs) was generated. LILRB3-specific mAbs bound to discrete epitopes in Ig-like domain 2 or 4. LILRB3 ligation on primary human monocytes by an agonistic mAb resulted in phenotypic and functional changes, leading to potent inhibition of immune responses in vitro, including significant reduction in T cell proliferation. Importantly, agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells. Our findings reveal powerful immunosuppressive functions of LILRB3 and identify it as an important myeloid checkpoint receptor.
Text
LILRB3 (ILT5) is a myeloid cell
- Version of Record
More information
e-pub ahead of print date: 1 September 2020
Published date: 1 September 2020
Additional Information:
Funding Information:
consultant for BioInvent International and receives research funding from BioInvent International. AR receives funding from BioInvent International. TS, UM, UT, BH, AL, MM, and BF are employees of BioInvent International.
Funding Information:
This work was supported by an iCASE studentship awarded to AR, BF, and MSC to support MY from the Biotechnology and Biological Sciences Research Council and BioInvent International AB, Sweden. AR was a recipient of a Blood Cancer UK Visiting Fellowship (number 14043). Work in the JT lab was supported by European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement 695551).
Publisher Copyright:
Copyright: © 2020, Yeboah et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
Keywords:
Immunology, Immunotherapy, Macrophages, Monocytes
Identifiers
Local EPrints ID: 444329
URI: http://eprints.soton.ac.uk/id/eprint/444329
ISSN: 2379-3708
PURE UUID: 686ef65e-650f-4b14-9e4a-4cbac9b84186
Catalogue record
Date deposited: 13 Oct 2020 16:39
Last modified: 06 Jun 2024 01:48
Export record
Altmetrics
Contributors
Author:
Muchaala Yeboah
Author:
Charys Papagregoriou
Author:
Des C. Jones
Author:
Hak Chan
Author:
Guangan Hu
Author:
Justine McPartlan
Author:
Christopher Mockridge
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics