not function by disrupting CD4:MHC class II interactions
transmits inhibitory signals via its cytoplasmic domain
Alternative Ligands
Galectin-3
Galectin-3-mediated suppression of CD8+ T cell-secreted IFN-γ in vitro
Galectin-3 is expressed by many cells within the tumor microenvironment
LSECtin
it promotes growth by inhibiting anti-tumor T-cell dependent responses
The interaction between LAG3 and LSECtin in melanoma cells was found to
inhibit IFN-γ production by antigen-specific effector T cells
α-synuclein preformed fibrils
trigger endocytosis into neurons
facilitate Parkinson's disease
LAG3 Expression
activated human T and NK cells
Persistent T cell activation in a chronic inflammatory environment, as in a tumor or during chronic viral infection, results in sustained co-expression of LAG3
resulting in a state of T cell dysfunction
thymic-derived tTregs
low expression in a resting state
preferentially expressed on tumor infiltrating Tregs
Tr1
Tr1 cells secrete high amounts of IL-10.
LAG3 contributes to Tr1 function
γδ T cells
A small percentage (~18%) of γδ T cells (固有免疫，抗肿瘤作用)
αβ T cells
TCRαβ+CD8αα+ IEL express significantly increased levels of LAG3
several additional hematopoietic cell
broad expression
pDC
活化后可快速产生大量Ⅰ型干扰素
thymic medulla and at the base of the cerebellum
bind α-synuclein fibrils
LAG3 Signaling
抑制基序 EP motif and KIEELE motif
MHCⅡ与表达LAG3的Treg结合抑制DC成熟，促进耐受
Regulation of LAG3 Expression and Function
LAG3 shedding
ADAM10/17-mediated LAG3 shedding
sLAG3 function
may serve as a prognostic biomarker as serum levels
a relevant indicator of enhanced LAG3 expression within inflammatory sites
Lysosomal degradation
be degraded in lysosomal compartments
be rapidly translocated to the surface upon TCR stimulation
blockade of lysosomal enzyme activity enhances surface expression
Physiological Role of LAG3
A negative regulator of T cell activation and function
KIEELE motif
LAG3 negatively controls T cell homeostasis
significant increase of SEB-reactive T cells was reported in the absence of LAG3
LAG3 may control the size of the memory T cell pool
Sendai virus experiment
LAG3 limits（promotes） self-tolerance
LAG3 blockade enhanced the accumulation of HA-specific CD8+ T cells
LAG3 expression on Tregs → maximal suppressive activity
promotes Treg differentiation
pDC
unclear
drive MDSC-mediated immunosuppression
NK iNKT
unclear
reduce NKT proliferation，impair IFN-γ production
Role of LAG3 in controlling Autoimmunity
LAG3 不足会导致自身免疫病加重
LAG3 blockade or genetic ablation resulted in an increased susceptibility to disease as a failure to maintain tolerance
Lag3–/– Pdcd1–/– mice succumb to a lethal systemic autoimmunity
a synergistic cooperation between LAG3 and PD1 in maintaining immune homeostasis and preventing autoimmunity
Role of LAG3 in mediating T cell exhaustion
functional exhaustion, lack of proliferation, CK secretion and cytolytic activity
Exhausted CD8+ T cells had a severe defect in cytokine production
control T cell proliferation/cell cycle progression → a state of hypofunction
Combinatorial blockade of LAG3 and PD1 enhanced antitumor immunity
LAG3 expression was upregulated with anti-PDL1 therapy，compensatorily
