Siglec-G-CD24 axis controls the severity of graft-versus-host disease in mice.
Activation of sialic-acid-binding immunoglobulin-like lectin-G (Siglec-G) by noninfectious damage-associated molecular patterns controls innate immune responses. However, whether it also regulates T-cell-mediated adaptive immune responses is not known. Graft-versus-host reaction is a robust adaptive immune response caused by allogeneic hematopoietic cell transplantation that have been activated by antigen-presenting cells (APCs) in the context of damaged host tissues following allogeneic hematopoietic cell transplantation. The role of infectious and noninfectious pattern recognition receptor-mediated activation in the induction and aggravation of graft-versus-host disease (GVHD) is being increasingly appreciated. But the role of pathways that control innate immune responses to noninfectious stimuli in modulating GVHD has heretofore not been recognized. We report that Siglec-G expression on host APCs, specifically on hematopoietic cells, negatively regulates GVHD in multiple clinically relevant murine models. Mechanistic studies with various relevant Siglec-G and CD24 knockout mice and chimeric animals, along with rescue experiments with novel CD24 fusion protein demonstrate that enhancing the interaction between Siglec-G on host APCs with CD24 on donor T cells attenuates GVHD. Taken together, our data demonstrate that Siglec-G-CD24 axis, controls the severity of GVHD and suggest that enhancing this interaction may represent a novel strategy for mitigating GVHD.
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
Tomomi
T
Toubai
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
Guoqing
G
Hou
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
Nathan
N
Mathewson
Department of Pathology, University of Florida College of Medicine, Gainesville, FL;
Chen
C
Liu
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
Ying
Y
Wang
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
Katherine
K
Oravecz-Wilson
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
Emily
E
Cummings
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
Corinne
C
Rossi
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
Rebecca
R
Evers
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
Yaping
Y
Sun
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
Julia
J
Wu
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI;
Sung Won
SW
Choi
OncoImmune, Inc., Rockville, MD; and.
Dexing
D
Fang
Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC.
Pan
P
Zheng
Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC.
Yang
Y
Liu
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
Pavan
P
Reddy
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000209:etiology / Q000378:metabolism* / Q000401:mortality; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D037102:Lectins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D011827:Radiation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012720:Severity of Illness Index; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
D051927:CD24 Antigen; D037102:Lectins; D011947:Receptors, Antigen, B-Cell; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C522403:Siglecg protein, mouse