LILRB receptor-mediated regulation of myeloid cell maturation and function

Abstract

The leukocyte immunoglobulin-like receptor (LILR) family comprises a set of paired immunomodulatory receptors expressed among human myeloid and lymphocyte cell populations. While six members of LILR subfamily A (LILRA) associate with membrane adaptors to signal via immunoreceptor tyrosine-based activating motifs (ITAM), LILR subfamily B (LILRB) members signal via multiple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIM). Ligand specificity of some LILR family members has been studied in detail, but new perspective into the immunoregulatory aspects of this receptor family in human myeloid cells has been limited. LILRB receptors and the murine ortholog, paired immunoglobulin-like receptor B (PIRB), have been shown to negatively regulate maturation pathways in myeloid cells including mast cells, neutrophils, dendritic cells, as well as B cells. Our laboratory further demonstrated in mouse models that PIRB regulated functional development of myeloid-derived suppressor cell and the formation of a tumor-permissive microenvironment. Based on observations from the literature and our own studies, our laboratory is focusing on how LILRs modulate immune homeostasis of human myeloid cells and how these pathways may be targeted in disease states. Integrity of this pathway in tumor microenvironments, for example, permits a myeloid phenotype that suppresses antitumor adaptive immunity. This review presents the evidence supporting a role of LILRs as myeloid cell regulators and ongoing efforts to understand the functional immunology surrounding this family.

LILRB3 (ILT5) is a myeloid checkpoint on myeloid cells that elicits profound immununomodulation

“…A selection of these mAb were then fluorochromelabelled and used to determine the LILRB3 expression profile of human peripheral blood; demonstrating predominant staining of monocytes and to a lesser extent granulocytes ( Fig. 1F and G), in agreement with previous reports (2,3,6). The immunophenotyping also revealed that LILRB3 expression was significantly higher on circulatory CD14 +hi /CD16 -'classical' and CD14 + /CD16 +low 'intermediate' monocytes compared with the more inflammatory CD14 + /CD16 +hi 'non-classical' monocytes ( Fig.…”

“…Those clones showing cross-reactivity to other human LILR family members were excluded. Immunoprofiling of circulatory leukocytes from healthy donors using these highly specific mAb confirmed the reported expression of LILRB3 on myelomonocytic and granulocytic cells, but not on lymphocytes (2,3,6). This pattern of expression on myeloid and granulocytic but not lymphoid cells was confirmed in a large cohort of independent donors (>50), suggesting that, despite the polymorphic nature of LILRB3 (2,9,43), the selected antibodies recognize many, if not all, variants, which is important for the development of these reagents for therapeutic applications.…”

“…The LILRB molecules are proposed to act as immune checkpoints serving to control and limit overt immune responses (3). In agreement with this, LILRB expression is increased in suppressive (also referred to as alternatively activated or M2) macrophages and tolerogenic dendritic cells (DCs) (11)(12)(13)(14)(15).…”

“…Molecules of the human leukocyte immunoglobulin (Ig)-like receptor (LILR) family, discovered over two decades ago (1,2), are expressed on leukocytes and are commonly dysregulated in a wide range of pathologies (3)(4)(5). There are five activating (LILRA1, 2, 4-6), five inhibitory (LILRB1-5) and one soluble (LILRA3) LILR that together regulate immune responses (3). They display two, or four, homologous C-2 type Ig-like extracellular domains, but differ in their transmembrane and cytoplasmic regions (2,6).…”

“…Among the inhibitory LILRBs, LILRB3 (ILT5/LIR3/CD85a), containing 4 extracellular Iglike domains and 4 intracellular ITIM motifs, represents an attractive immunomodulatory target because of its relative restriction to, and high expression on, myeloid cells (3,4).…”