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Human inhibitory leukocyte Ig-like receptors: from immunotolerance to immunotherapy
Calvin D. De Louche, Ali Roghanian
Calvin D. De Louche, Ali Roghanian
Published January 25, 2022
Citation Information: JCI Insight. 2022;7(2):e151553. https://doi.org/10.1172/jci.insight.151553.
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Review

Human inhibitory leukocyte Ig-like receptors: from immunotolerance to immunotherapy

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Abstract

In recent decades, immunotherapeutic strategies have been used to treat a wide range of pathologies, many of which were previously incurable, such as cancer and autoimmune disorders. Despite this unprecedented success, a considerable number of patients fail to respond to currently approved immunotherapies or develop resistance over time. Therefore, there is an urgent need to develop the next generation of immune-targeted therapies. Various members of the Ig superfamily play essential roles in regulating leukocyte functions. One such group, the leukocyte Ig-like receptors (LILRs), have been implicated in both innate and adaptive immune regulation. Human inhibitory LILRs (LILRBs) are primarily expressed on leukocytes and mediate their signaling through multiple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. Engagement of LILRBs by endogenous and pathogenic ligands can markedly suppress immune responses, leading to tolerance or immunoevasion, whereas blocking these inhibitory receptors can potentiate immune responses. In this Review, we discuss the immunoregulatory functions of human LILRBs and the potential of targeting them to manipulate immune responses in various pathologies.

Authors

Calvin D. De Louche, Ali Roghanian

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Figure 1

LILRB1-mediated regulation of myeloid and lymphoid cells.

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LILRB1-mediated regulation of myeloid and lymphoid cells.
(A) Ligation o...
(A) Ligation of LILRB1 on tumor-associated macrophages (TAMs) by HLA class I/β2-microglobulin (β2m) expressed on tumor cells inhibits the phagocytic activity of TAMs, resulting in reduced immunosurveillance and enhanced tumor cell immunoevasion. (B) Peripheral NK cells from some patients with cancer express markedly high levels of LILRB1 molecules, which, upon engagement with HLA class I on tumor cells, leads to suppression of NK cell activity. Blocking this interaction with antagonistic mAbs has been experimentally shown to enhance the tumoricidal activity of NK cells against solid tumors and hematological malignancies. On the other hand, LILRB1-mediated inhibition of NK cells is an important mechanism by which overt immune responses in pregnancy may be controlled to avoid insult to the fetus. (C) Ligation of LILRB1 by HLA class I is capable of inhibiting B cell function, most notably reducing the secretion of auto/alloantibodies.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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