TY - JOUR
T1 - Siglec-G represses DAMP-mediated effects on T cells
AU - Toubai, Tomomi
AU - Rossi, Corinne
AU - Oravecz-Wilson, Katherine
AU - Zajac, Cynthia
AU - Liu, Chen
AU - Braun, Thomas
AU - Fujiwara, Hideaki
AU - Wu, Julia
AU - Sun, Yaping
AU - Brabbs, Stuart
AU - Tamaki, Hiroya
AU - Magenau, John
AU - Zheng, Pang
AU - Liu, Yang
AU - Reddy, Pavan
N1 - Funding Information:
This work was supported by NIH grants HL090775, CA173878, HL128046, and CA203542, and an American Society of Blood and Marrow Transplantation New Investigator Award (to T.T.).
Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.
PY - 2017/7/20
Y1 - 2017/7/20
N2 - The role of negative regulators or suppressors of the damage-associated molecular pattern–mediated (DAMP-mediated) stimulation of innate immune responses is being increasingly appreciated. However, the presence and function of suppressors of DAMP-mediated effects on T cells, and whether they can be targeted to mitigate T cell–dependent immunopathology remain unknown. Sialic acid–binding immunoglobulin-like lectin G (Siglec-G) is a negative regulator of DAMP-mediated responses in innate immune cells, but its T cell–autonomous role is unknown. Utilizing loss-of-function–based (genetic knockout) and gain-of-function–based (agonist) approaches, we demonstrate that in the presence of certain DAMPs, Siglec-G suppressed in vitro and in vivo T cell responses. We also demonstrate that its T cell–autonomous role is critical for modulating the severity of the T cell–mediated immunopathology, graft-versus-host disease (GVHD). Enhancing the Siglec-G signaling in donor T cells with its agonist, a CD24Fc fusion protein, ameliorated GVHD while preserving sufficient graft-versus-tumor (GVT) effects in vivo. Collectively, these data demonstrate that Siglec-G is a potentially novel negative regulator of T cell responses, which can be targeted to mitigate GVHD.
AB - The role of negative regulators or suppressors of the damage-associated molecular pattern–mediated (DAMP-mediated) stimulation of innate immune responses is being increasingly appreciated. However, the presence and function of suppressors of DAMP-mediated effects on T cells, and whether they can be targeted to mitigate T cell–dependent immunopathology remain unknown. Sialic acid–binding immunoglobulin-like lectin G (Siglec-G) is a negative regulator of DAMP-mediated responses in innate immune cells, but its T cell–autonomous role is unknown. Utilizing loss-of-function–based (genetic knockout) and gain-of-function–based (agonist) approaches, we demonstrate that in the presence of certain DAMPs, Siglec-G suppressed in vitro and in vivo T cell responses. We also demonstrate that its T cell–autonomous role is critical for modulating the severity of the T cell–mediated immunopathology, graft-versus-host disease (GVHD). Enhancing the Siglec-G signaling in donor T cells with its agonist, a CD24Fc fusion protein, ameliorated GVHD while preserving sufficient graft-versus-tumor (GVT) effects in vivo. Collectively, these data demonstrate that Siglec-G is a potentially novel negative regulator of T cell responses, which can be targeted to mitigate GVHD.
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U2 - 10.1172/jci.insight.92293
DO - 10.1172/jci.insight.92293
M3 - Article
C2 - 28724800
AN - SCOPUS:85061109941
VL - 2
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 14
M1 - e92293
ER -