Recruitment of C-terminal Src kinase by the leukocyte inhibitory receptor CD85j

Sayós, Joan; Martínez-Barriocanal, Águeda; Kitzig, Friederike; Bellón, Teresa; López‐Botet, Miguel

doi:10.1016/j.bbrc.2004.09.097

Cited by 38 publications

(29 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ITIM-containing SHP-2 interacting transmembrane adaptor protein (SIT) binds Csk, but via a tyrosine residue outside the ITIM [28]. However, previously, it was reported that signal regulatory protein (SIRP)a and Ig-like transcript (ILT)-2 bind Csk [29,30]. In contrast, KIR3DL1 was reported not to recruit Csk [31].…”

Section: Discussionmentioning

confidence: 99%

Leukocyte‐associated Ig‐like receptor‐1 has SH2 domain‐containing phosphatase‐independent function and recruits C‐terminal Src kinase

et al. 2005

View full text Add to dashboard Cite

Most inhibitory receptors in the immune system contain one or several immunoreceptor tyrosine-based inhibitory motifs (ITIM) and recruit the SH2 domain-containing phosphatases SHP-1, SHP-2 and/or SHIP, which are generally believed to be essential for the inhibitory function. However, it has not been systematically investigated whether ITIM-bearing receptors exert their function through alternative interactions. Here we describe that leukocyte-associated Ig-like receptor (LAIR)-1 has inhibitory function in DT40 chicken B cells that lack both SHP-1 and SHP-2. In addition, we found that LAIR-1 did not recruit SHIP upon phosphorylation. Thus, LAIR-1 can function independently from SH2 domain-containing phosphatases and must recruit at least one other signaling molecule. Using a yeast-tri-hybrid system, we found that phosphorylated LAIR-1 bound the C-terminal Src kinase (Csk). The interaction required the SH2 domain of Csk and phosphorylation of the tyrosine in the N-terminal ITIM of LAIR-1. We propose that Csk is an additional player in the regulation of the immune system by ITIMbearing receptors. IntroductionAn appropriate response of the immune system depends on a balance between activating and inhibitory signals. Inhibitory receptors play an important role in the regulation of immune cells. This is illustrated by the fact that mutations in inhibitory receptors or in the molecules through which they signal, are associated with autoimmune disease [1]. Most inhibitory receptors in the immune system contain one or several immunoreceptor tyrosine-based inhibitory motifs (ITIM). This motif has the consensus sequence (I/V/L/S)-x-Y-x-x-(L/ V/I), where x represents any amino acid [2]. Upon engagement, ITIM-bearing receptors become phosphorylated and recruit the SH2 domain-containing inositol phosphatase SHIP and/or the SH2 domaincontaining tyrosine phosphatases SHP-1 and SHP-2. The phosphatases subsequently dephosphorylate and thereby inactivate key molecules involved in cellular activation [2,3]. It is widely believed that the recruitment of SH2 domain-containing phosphatases is required for the inhibitory function of ITIM-bearing receptors. However, several studies, including our previous work on leukocyte-associated Ig-like receptor (LAIR)-1, suggest that the phosphatases are not the sole down-stream effectors of ITIM-bearing receptors.LAIR-1 is an ITIM-bearing receptor that is broadly expressed in the immune system [4] and functions as an inhibitory receptor on NK cells, T cells and B cells [4][5][6][7][8][9]. In addition, LAIR-1 inhibits the differentiation of peripheral blood precursors towards dendritic cells [10] and induces apoptosis in myeloid leukemia cells [11,12] Here we show that LAIR-1 has an inhibitory capacity in SHP-1-and SHP-2-deficient DT40 chicken B cells and does not recruit SHIP. This indicates that, in contrast to the established dogma, LAIR-1 has an inhibitory function independent of SH2 domain-containing phosphatases. Therefore, we searched for other LAIR-1-interacting proteins. Using a yeast-tri...

show abstract

Section: Discussionmentioning

confidence: 99%

Leukocyte‐associated Ig‐like receptor‐1 has SH2 domain‐containing phosphatase‐independent function and recruits C‐terminal Src kinase

et al. 2005

View full text Add to dashboard Cite

show abstract

“…hLAIR-1 and mLAIR-1 recruit C-terminal Csk [33], a known negative regulator of immune cell function that inactivates Src family kinases [36]. Csk association is also reported for other ITIM-bearing receptors, including signal regulatory protein-␣, Ig-like transcript-2, and Fc␥RIIB [33,37,38] but not KIR3DL1 [39]. Thus, LAIR-1-mediated inhibition is not solely dependent on phosphatases, and Csk may be the key downstream effector of LAIR-1 in cells where phosphatase activity is limited [33].…”

Section: Lair-1 Recruitsmentioning

confidence: 89%

The inhibitory collagen receptor LAIR-1 (CD305)

Meyaard

2007

Journal of Leukocyte Biology

246

View full text Add to dashboard Cite

“…LILRB1 is associated with the hematopoietic phosphatase SHP-1, which is known to inhibit activation by receptors such as FCGR in monocytes, 25 OSCAR in DCs, 26 and the TCR in CD8 T cells. 27 The inhibitory kinase Csk has also been demonstrated to be recruited by the cytoplasmic tail of LILRB1 28 and may also regulate the TLR4 pathway. 29 These putative intracellular signaling events require further investigation.…”

Section: Discussionmentioning

confidence: 99%

The inhibitory receptor LILRB1 modulates the differentiation and regulatory potential of human dendritic cells

Young

Waller

Patel

et al. 2008

Blood

View full text Add to dashboard Cite

IntroductionDendritic cells (DCs) play pivotal roles in the initiation, regulation, and maintenance of immune responses. 1 Activation of DCs through toll-like receptors (TLRs) for "infectious nonself" or other "danger" signals normally initiates a process of cellular differentiation resulting in "mature" DCs capable of stimulating T-cell and natural killer (NK)-cell responses. It has also been proposed that DCs are intimately involved in the prevention of inappropriate immune responses to "self"-antigens. 2 How this is achieved is not well known, but it is clear that DCs in a quiescent "immature" state can potentially control autoimmune attacks, through secretion of immunosuppressive cytokines such as IL-10 or TGF-␤, for example, or by controlling the induction of CD4 ϩ CD25 ϩ regulatory T cells.Recent studies have suggested a role for human leukocyte Ig-like receptors (LILRs, also known as ILT, LIR, or CD85) in regulating the function of myeloid cells, potentially implicating these molecules in the control of immune responses. [3][4][5] LILRs are encoded by a set of genes within the leukocyte receptor cluster on chromosome 19q13.4, adjacent to the killer Ig-like receptor (KIR) genes that are responsible for controlling NK-and CD8 T-cell survival and effector functions. 6 Similar to the KIR, the only known ligands for certain LILR molecules are "self"-HLA class I molecules. Ligation of these receptors results either in diminution of intracellular signaling by ITIM-associated phosphatase activity for inhibitory receptors with a long cytoplasmic tail or in ITAMassociated signaling through adaptor molecules recruited by activating receptors with a short cytoplasmic tail.Unlike KIRs, which are expressed clonally to form a variegated repertoire by NK cells, LILR molecules appear to be almost ubiquitously expressed by myeloid cells including most types of DCs, with the exception of plasmacytoid DCs. 7 Typically, human DCs for experimental and/or therapeutic purposes are obtained by culturing monocytes in defined cytokines, followed by maturation with TLR agonists such as LPS and/or other stimuli. 8 Here we demonstrate that continuous ligation of the inhibitory receptor LILRB1 (ILT2, LIR1, CD85j) 9 by mimics of "self"-MHC molecules dramatically alters the cellular differentiation program and subsequent responses to the "infectious nonself" TLR agonist LPS, the capacity to induce and regulate T-cell responses, and susceptibility to cell death. Methods Generation of monocyte-derived DCsDCs were derived from peripheral blood monocytes by culture for 6 days in RPMI 1640 containing penicillin (100 U/mL), streptomycin (100 g/mL), and 1% autologous plasma, 50 ng/mL recombinant human granulocytemacrophage colony-stimulating factor (GM-CSF; Peprotech, London, United Kingdom), and 50 ng/mL recombinant human IL-4 (Peprotech). Half of the medium was replaced with fresh cytokines every 2 days until day 6 of culture, when bacterial LPS (Sigma, Poole, United Kingdom) was added to a concentration of 1 ng/mL for 24 hours as required.To...

show abstract

Recruitment of C-terminal Src kinase by the leukocyte inhibitory receptor CD85j

Cited by 38 publications

References 29 publications

Leukocyte‐associated Ig‐like receptor‐1 has SH2 domain‐containing phosphatase‐independent function and recruits C‐terminal Src kinase

Leukocyte‐associated Ig‐like receptor‐1 has SH2 domain‐containing phosphatase‐independent function and recruits C‐terminal Src kinase

The inhibitory collagen receptor LAIR-1 (CD305)

The inhibitory receptor LILRB1 modulates the differentiation and regulatory potential of human dendritic cells

Contact Info

Product

Resources

About