High affinity soluble ILT2 receptor: a potent inhibitor of CD8+ T cell activation

Moysey, Ruth; Li, Yang; Paston, Samantha; Baston, Emma; Sami, Malkit; Cameron, Brian; Gavarret, Jessie; Todorov, Penio; Vuidepot, Annelise; Dunn, Steven M.; Pumphrey, Nicholas J.; Adams, Katherine J.; Yuan, Fang; Dennis, Rebecca; Sutton, Deborah H.; Johnson, A.; Brewer, Joanna E.; Ashfield, Rebecca; Lissin, Nikolai; Jakobsen, Bent K.

doi:10.1007/s13238-010-0144-5

Cited by 6 publications

(5 citation statements)

References 34 publications

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“…As LAG-3 binding to pHLA-II molecules has been shown to block consequent CD4 binding at the cell surface [19], competition between LAG-3 and CD4 for pHLA-II binding would favor engagement by LAG-3, potentially contributing to LAG-3 mediated T cell inhibition. It is noteworthy that the LAG-3 affinity for pHLA-II reported here (K D = 6.9-13.1 μM) is similar to that of the pHLA-I co-inhibitory receptor, ILT2 (K D = 7 μM) [26], which interferes with pHLA-I restricted T cell function [39]. We also demonstrated that pHLA-DR1 multimers weakly stain LAG-3 + cells.…”

Section: Discussionsupporting

confidence: 73%

“…Although informative, it is difficult to rule out the contributions of other molecules at the cell surface in shaping these interactions [20,21]. Further experimental evidence, showing that LAG-3 can block the pHLA-II-CD4 interaction, suggested that LAG-3 might bind to pHLA-II at a similar site to CD4 [22,23], analogous to the characteristics of Ig-like transcript 2 (ILT2) and CD8 that compete for binding to pHLA-I [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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Molecular characterization of HLA class II binding to the LAG‐3 T cell co‐inhibitory receptor

et al. 2020

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Immune checkpoint inhibitors (antibodies that block the T cell co-inhibitory receptors PD-1/PD-L1 or CTLA-4) have revolutionized the treatment of some forms of cancer. Importantly, combination approaches using drugs that target both pathways have been shown to boost the efficacy of such treatments. Subsequently, several other T cell inhibitory receptors have been identified for the development of novel immune checkpoint inhibitors. Included in this list is the co-inhibitory receptor lymphocyte activation gene-3 (LAG-3), which is upregulated on T cells extracted from tumor sites that have suppressive or exhausted phenotypes. However, the molecular rules that govern the function of LAG-3 are still not understood. Using surface plasmon resonance combined with a novel bead-based assay (AlphaScreen TM), we demonstrate that LAG-3 can directly and specifically interact with intact human leukocyte antigen class II (HLA-II) heterodimers. Unlike the homologue CD4, which has an immeasurably weak affinity using these biophysical approaches, LAG-3 binds with low micromolar affinity. We further validated the interaction at the cell surface by staining LAG-3 + cells with pHLA-II-multimers. These data provide new insights into the mechanism by which LAG-3 initiates T cell inhibition.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Molecular characterization of HLA class II binding to the LAG‐3 T cell co‐inhibitory receptor

et al. 2020

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“…Our data suggest that autoreactive CD8 + T-cells can be preferentially targeted using blocking anti-CD8 antibodies. Additional modalities could also be employed based on the underlying biology, such as rationally designed small molecular inhibitors and soluble versions of the inhibitory immunoglobulin-like transcript 2 (ILT2) receptor 58 . These approaches hold the potential to suppress pathogenic CD8 + T-cell-mediated autoimmunity without the attendant side effects that complicate standard therapeutic interventions.…”

Section: Discussionmentioning

confidence: 99%

Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies

Clement

Pearson

Gras

et al. 2016

Sci Rep

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CD8+ T-cells play a role in the pathogenesis of autoimmune diseases such as multiple sclerosis and type 1 diabetes. However, drugs that target the entire CD8+ T-cell population are not desirable because the associated lack of specificity can lead to unwanted consequences, most notably an enhanced susceptibility to infection. Here, we show that autoreactive CD8+ T-cells are highly dependent on CD8 for ligand-induced activation via the T-cell receptor (TCR). In contrast, pathogen-specific CD8+ T-cells are relatively CD8-independent. These generic differences relate to an intrinsic dichotomy that segregates self-derived and exogenous antigen-specific TCRs according to the monomeric interaction affinity with cognate peptide-major histocompatibility complex class I (pMHCI). As a consequence, “blocking” anti-CD8 antibodies can suppress autoreactive CD8+ T-cell activation in a relatively selective manner. These findings provide a rational basis for the development and in vivo assessment of novel therapeutic strategies that preferentially target disease-relevant autoimmune responses within the CD8+ T-cell compartment.

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“…Following a CMV infection, LILRB1 is mainly expressed on terminally differentiated effector (TEMRA) CD8+ T cells and correlates with “memory inflation”0 . LILRB1 inhibits the CD8+ CTL response, and a high affinity, soluble LILRB1 has been used to study the activation mechanisms of various subsets of CTLs . Inhibition of LILRB1 promotes CD8+ T cell effector responses in the ageing immune system .…”

Section: Lilrb1 Expression On Myeloid Cellsmentioning

confidence: 99%

The MHC class I‐LILRB1 signalling axis as a promising target in cancer therapy

et al. 2019

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Immune checkpoint inhibitors are among the newest, cutting-edge methods for the treatment of cancer. Currently, they primarily influence T cell adaptive immunotherapy targeting the PD-1/PD-L1 and CTLA-4/B7 signalling pathways. These inhibitors fight cancer by reactivating the patient's own adaptive immune system, with good results in many cancers. With the discovery of the "Don't Eat Me" molecule, CD47, antibody-based drugs that target the macrophage-related innate immunosuppressive signalling pathway, CD47-SIRPα, have been developed and have achieved stunning results in the laboratory and the clinic, but there remain unexplained instances of tumour immune escape. While investigating the immunological tolerance of cancer to anti-CD47 antibodies, a second "Don't Eat Me" molecule on tumour cells, beta 2 microglobulin (β2m), a component of MHC class I, was described. Some tumour cells reduce their surface expression of MHC class I to escape T cell recognition.However, other tumour cells highly express β2m complexed with the MHC class I heavy chain to send a "Don't Eat Me" signal by binding to leucocyte immunoglobulin-like receptor family B, member 1 (LILRB1) on macrophages, leading to a loss of immune surveillance. Investigating the mechanisms underlying this immunosuppressive MHC class I-LILRB1 signalling axis in tumour-associated macrophages will be useful in developing therapies to restore macrophage function and control MHC class I signalling in patient tumours. The goal is to promote adaptive immunity while suppressing the innate immune response to tumours. This work will identify new therapeutic targets for the development of pharmaceutical-based tumour immunotherapy.

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High affinity soluble ILT2 receptor: a potent inhibitor of CD8+ T cell activation

Cited by 6 publications

References 34 publications

Molecular characterization of HLA class II binding to the LAG‐3 T cell co‐inhibitory receptor

Molecular characterization of HLA class II binding to the LAG‐3 T cell co‐inhibitory receptor

Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies

The MHC class I‐LILRB1 signalling axis as a promising target in cancer therapy

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