LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems.
Lymphocyte activation gene-3 (LAG-3) is a cell-surface molecule with diverse biologic effects on T cell function. We recently showed that LAG-3 signaling is important in CD4+ regulatory T cell suppression of autoimmune responses. Here, we demonstrate that LAG-3 maintains tolerance to self and tumor antigens via direct effects on CD8+ T cells using 2 murine systems. Naive CD8+ T cells express low levels of LAG-3, and expression increases upon antigen stimulation. Our data show increased levels of LAG-3 protein on antigen-specific CD8+ T cells within antigen-expressing organs or tumors. In vivo antibody blockade of LAG-3 or genetic ablation of the Lag-3 gene resulted in increased accumulation and effector function of antigen-specific CD8+ T cells within organs and tumors that express their cognate antigen. Most notably, combining LAG-3 blockade with specific antitumor vaccination resulted in a significant increase in activated CD8+ T cells in the tumor and disruption of the tumor parenchyma. A major component of this effect was CD4 independent and required LAG-3 expression by CD8+ T cells. Taken together, these data demonstrate a direct role for LAG-3 on CD8+ T cells and suggest that LAG-3 blockade may be a potential cancer treatment.
Grosso
Joseph F
JF
Sidney Kimmel Comprehensive Cancer Center and Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Kelleher
Cristin C
CC
Harris
Timothy J
TJ
Maris
Charles H
CH
Hipkiss
Edward L
EL
De Marzo
Angelo
A
Anders
Robert
R
Netto
George
G
Getnet
Derese
D
Bruno
Tullia C
TC
Goldberg
Monica V
MV
Pardoll
Drew M
DM
Drake
Charles G
CG
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017634:Self Tolerance / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D000093322:Lymphocyte Activation Gene 3 Protein