ライフサイエンスコーパス: LAIR-1

1 LAIR-1 is a 32 kDa transmembrane glycoprotein with a sin

2 LAIR-1 is an inhibitory receptor on immune cells that re

3 LAIR-1 is hyper-phosphorylated on tyrosyl residues in ce

4 LAIR-1 recruits SHP-1 and SHP-2 phosphatases upon activa

5 LAIR-1 signaling in ILC2s was mediated via inhibitory pa

6 LAIR-1(-/-) mice have lower serum levels of IgG1 and, in

7 LAIR-1-mediated inhibitory function was increased after

8 e-associated immunoglobulin-like receptor 1 (LAIR-1) but also indicates significant differences that

9 e-associated immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory receptor considered to be an im

10 e-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory receptor for C1q.

11 e-associated immunoglobulin-like receptor 1 (LAIR-1).

12 and leukocyte-associated Ig-like receptor 1 (LAIR-1; CD305), an inhibitory receptor expressed on hema

13 e-associated immunoglobulin-like receptor-1 (LAIR-1) in combination with blockade of TGF-beta and pro

14 tor leukocyte-associated Ig-like receptor-1 (LAIR-1) in vitro delivers an inhibitory signal that is a

15 Leukocyte associated Ig-like receptor-1 (LAIR-1) is a surface molecule expressed on human mononuc

16 to leukocyte-associated Ig-like receptor-1 (LAIR-1), a recently cloned transmembrane protein.

17 e-associated immunoglobulin-like receptor-1 (LAIR-1), that is constitutively expressed on the majorit

18 led leukocyte-associated Ig-like receptor-1 (LAIR-1).

19 e-associated immunoglobulin-like receptor-1 (LAIR-1).

20 Because LAIR-1(+/+) and LAIR-1(-/-) T cells traffic with equal proficiency to pe

21 ferences in the responses of LAIR-1(-/-) and LAIR-1(+/+) mice were observed.

22 itory pathways, including SHP1/PI3K/AKT, and LAIR-1 deficiency led to exacerbated ILC2-dependent AHR

23 receptors, glycoprotein VI, alpha2beta1, and LAIR-1, determines a decrease in MK migration due to the

24 Whole C1q is required to crosslink CD33 and LAIR-1 and concurrently activate CD33/LAIR-1 inhibitory

25 cence microscopy demonstrated that MARCO and LAIR-1 interacted in cis on THP-1 macrophages.

26 MARCO and LAIR-1 were coexpressed by human macrophages in tumors a

27 ecause C1q contains collagen-like motifs and LAIR-1 is a universal collagen receptor, we hypothesized

28 g and tumor-associated collagen products and LAIR-1 and LAIR-2 as prognostic biomarkers in advanced O

29 is mediated through a complex with RAGE and LAIR-1 and depends on relative levels of C1q and HMGB1.

30 etramolecular complex cross-linking RAGE and LAIR-1 and directing monocytes to an antiinflammatory ph

31 f HMGB1 plus C1q, which cross-links RAGE and LAIR-1 and polarizes monocytes to an antiinflammatory ph

32 lvin D1, and resolvin D2 through a RAGE- and LAIR-1-dependent pathway.

33 Wild-type and LAIR-1 knockout mice were intranasally challenged with I

34 e intracellular signals when ligated by anti-LAIR-1 mAb, but only LAIR-1 wt cells respond to collagen

35 "effector" T cells, can be inhibited by anti-LAIR-1 mAb.

36 As LAIR-1(-/-) mice age, the splenic T cell population show

37 Because LAIR-1(+/+) and LAIR-1(-/-) T cells traffic with equal p

38 Both LAIR-1 wt and R65K cells can generate intracellular sign

39 The high abundance of both LAIR-1 and its ligands suggests tight regulation of this

40 MARCO on human macrophages, it reduced both LAIR-1 binding and the LAIR-1 signaling response to coll

41 mproved inhibition, and three domains (BTLA, LAIR-1, and SIGLEC-9) each suppressed CAR T function but

42 ition motifs that are both phosphorylated by LAIR-1 activation, and immunoprecipitation experiments r

43 bition of DC differentiation was reversed by LAIR-1 siRNA.

44 in trans and induced inhibitory signaling by LAIR-1 in human natural killer (NK) cells.

45 33 and LAIR-1 and concurrently activate CD33/LAIR-1 inhibitory motifs.

46 sting further biological control of C1q-CD33/LAIR-1 processes.

47 r C1q binds to CD33 and if C1q mediates CD33/LAIR-1 crosslinking.

48 SF, but not DC growth factors, sustains CD33/LAIR-1 expression on both healthy and SLE cells suggesti

49 nsistent with defective self-tolerance, CD33/LAIR-1 expression is reduced in systemic lupus erythemat

50 with LAIR-1 wild-type (wt)-expressing cells, LAIR-1 R65K cells show markedly reduced binding to colla

51 In addition to NK cells, LAIR-1 is expressed on T cells, B cells, macrophages, an

52 public human datasets shows that collagens, LAIR-1 and LAIR-2 have unique and overlapping associatio

53 showed that, under physiological conditions, LAIR-1 links more closely to the common genes in mouse t

54 s other than that of the broadly distributed LAIR-1/p40 molecule.

55 Finally, B6.DR1/LAIR-1(-/-) and B6.DR1/LAIR-1(+/+) mice were challenged for CIA and mean severi

56 Finally, B6.DR1/LAIR-1(-/-) and B6.DR1/LAIR-1(+/+) mice were challenged

57 ing LAIR-1 Abs suppresses CIA whereas B6.DR1/LAIR-1(-/-) mice develop more severe arthritis than wild

58 When B6.DR1/LAIR-1(-/-) mice were immunized with type II collagen th

59 ient mice, 2) Jurkat cells expressing either LAIR-1 mutants or C-terminal Src kinase (CSK) mutants, a

60 d we also found that Tyr-251 is critical for LAIR-1's inhibitory function.

61 Thus, C1q is a functional ligand for LAIR-1 restricting immune cell differentiation and activ

62 Here, we identified MARCO as a ligand for LAIR-1.

63 thesized that C1q is a functional ligand for LAIR-1.

64 (TCR) signaling, we compared 1) T cells from LAIR-1-sufficient and -deficient mice, 2) Jurkat cells e

65 the in vivo function of LAIR-1, we generated LAIR-1(-/-) mice.

66 To determine how LAIR-1 affects T-cell receptor (TCR) signaling, we compa

67 itation experiments revealed that Tyr-251 in LAIR-1 binds CSK.

68 urs, implying that the species difference in LAIR-1 genetic pathways could not be primarily attribute

69 urified CD4(+) cells that were sufficient in LAIR-1, CD3-induced cytokine secretion was significantly

70 0, a bivalent LAIR-2 construct that inhibits LAIR-1-collagen binding, would rescue neutrophil-driven

71 Interestingly, LAIR-1 was expressed and inducible in human ILC2s, and k

72 , this study opens the door for insight into LAIR-1 functions inside the human body, and raises conce

73 Collagen motifs ligate LAIR-1, an inhibitory SHP-1-dependent checkpoint broadly

74 Like LAIR-1, CD33 inhibitory immunoreceptors are highly expre

75 Likewise, LAIR-1 R65K protein has decreased avidity for cells expr

76 ing protein of SHP-1 on the plasma membrane, LAIR-1 may play an important role in hematopoietic cell

77 cell cytokine response through the action of LAIR-1.

78 When inhibitory domains of LAIR-1 or SIGLEC-9 were combined with PD-1 into a single

79 that defective expression or dysfunction of LAIR-1, a novel immunoinhibitory receptor for collagen,

80 colitis, were used to examine the effect of LAIR-1 deficiency, and no differences in the responses o

81 Finally, engagement of LAIR-1 by physiologic ligand C1q significantly reduced I

82 im here was to investigate the expression of LAIR-1 and assess its role in human and murine ILC2s.

83 express two biochemically distinct forms of LAIR-1, which we now show are likely alternative splice

84 To study the in vivo function of LAIR-1, we generated LAIR-1(-/-) mice.

85 We next studied the impact of LAIR-1 deficiency on AHR and lung inflammation by using

86 ic mice were used to study the importance of LAIR-1 in autoimmune arthritis.

87 1 and LAIR-2 (CD306), a soluble inhibitor of LAIR-1.

88 e, Arg65, is critical for the interaction of LAIR-1 with collagens.

89 er, we found that the in vivo interaction of LAIR-1 with LAIR-2 rarely occurs, implying that the spec

90 en, which correlates with a reduced level of LAIR-1 polarization to the site of interaction with coll

91 Cross-linking of LAIR-1 on human T cell clones results in inhibition of c

92 responsible for tyrosine phosphorylation of LAIR-1 and recruitment of SHP-1.

93 its collagen tail trigger phosphorylation of LAIR-1 immunoreceptor tyrosine-based inhibitory motifs (

94 responsible for tyrosine phosphorylation of LAIR-1 may belong to the Src family since PP1, a Src fam

95 The intracellular region of LAIR-1 contains two immunoreceptor tyrosine-based inhibi

96 Our results identify MARCO as a regulator of LAIR-1 signaling and suggest that the induction of MARCO

97 ency, and no differences in the responses of LAIR-1(-/-) and LAIR-1(+/+) mice were observed.

98 experimental data in relation to the role of LAIR-1 immune regulation may be overestimated when appli

99 manized mice were used to assess the role of LAIR-1 in human ILC2s.

100 We analyzed the variation of LAIR-1 genetic pathways in murine versus human internal

101 he effect of a conservative R65K mutation on LAIR-1 ligand binding and function.

102 ls when ligated by anti-LAIR-1 mAb, but only LAIR-1 wt cells respond to collagens or matrigel.

103 Splenocytes from wild-type or LAIR-1(-/-) mice were stimulated with soluble anti-CD3 A

104 Tyrosine-phosphorylated LAIR-1 specifically interacts with SHP-1 but not with SH

105 Like engagement of the ITIM-bearing receptor LAIR-1/p40, cross-linking of FDF03 inhibited calcium mob

106 d to human killer cell inhibitory receptors, LAIR-1 does not appear to recognize human leukocyte anti

107 ed on immune cells, and that LAIR-2 releases LAIR-1-mediated immune suppression.

108 es could enhance their function by releasing LAIR-1-mediated inhibition.

109 Treatment with stimulating LAIR-1 Abs suppresses CIA whereas B6.DR1/LAIR-1(-/-) mic

110 y binding collagen with higher affinity than LAIR-1.

111 We have demonstrated that LAIR-1 is inducible on activated ILC2s and downregulates

112 n together, these observations indicate that LAIR-1 plays a role in regulating immune cells and sugge

113 Our results indicated that LAIR-1 engagement by collagen or by complement C1q (C1Q,

114 This indicates that LAIR-1 provides a mechanism of regulation of effector T

115 We propose that LAIR-1 activation may be a strategy for controlling infl

116 rface plasmon resonance analyses showed that LAIR-1 R65K protein has markedly reduced avidity for col

117 These data suggest that LAIR-1 may be a potential therapeutic target for suppres

118 ike region (CLR) engaging and activating the LAIR-1 inhibitory immunoreceptor represents a non-comple

119 ages, it reduced both LAIR-1 binding and the LAIR-1 signaling response to collagen.

120 ptive transfer experiments, we confirmed the LAIR-1-mediated regulation of ILC2s in vivo.

121 we demonstrate that CSK is essential for the LAIR-1-induced inhibition of the human TCR signal transd

122 es upon activation, and cross-linking of the LAIR-1 antigen on natural killer (NK) cells results in s

123 Thus, LAIR-1 functions as an inhibitory receptor not only on N

124 exhaustion or inhibition (PD-1, LAG-3, TIM3, LAIR-1, and CTLA-4) and HBV-specific T cells.

125 However, in contrast to LAIR-1/p40, cross-linking of FDF03 did not inhibit GM-CS

126 Treatment with a stimulatory mAb to LAIR-1 also significantly attenuated CIA in the LAIR(+/+

127 e treated with either the stimulatory mAb to LAIR-1 or a hamster IgG control.

128 mall cell lung cancer showed highly variable LAIR-1 staining in both tumor cell and immune infiltrate

129 hat NC410 binds to collagen-rich areas where LAIR-1(+) immune cells are localized.

130 pressed in the presence of collagen, whereas LAIR-1-deficient splenocytes had no attenuation.

131 hat C1q and its collagen tail associate with LAIR-1 and LAIR-2 (CD306), a soluble inhibitor of LAIR-1

132 Compared with LAIR-1 wild-type (wt)-expressing cells, LAIR-1 R65K cell

133 ed avidity for collagen type I compared with LAIR-1 wt.

134 MARCO interacted with LAIR-1 in trans and induced inhibitory signaling by LAIR

135 s promote immune evasion by interacting with LAIR-1 expressed on immune cells, and that LAIR-2 releas

136 The discovery of C1q interactions with LAIR-1 and LAIR-2 lends much needed insight into molecul