Leukocyte Immunoglobulin-like Receptor Family Research Articles

Abstract 1362: IOMX-0675, a LILRB1 and LILRB2 cross-specific antibody, effectively repolarizes immunosuppressive myeloid cells and activates T cells leading to potent tumor cell killing

Abstract Recently, myeloid checkpoints in the tumor microenvironment have gained increased attention in the context of tumor immune evasion. LILRB1 (ILT2) and LILRB2 (ILT4) are immunosuppressive receptors of the leukocyte immunoglobulin-like receptor (LILR) family that recognize both classical and non-classical MHC-I molecules (e.g., HLA-G). While tumor-infiltrating myeloid cells express both LILRB1 and LILRB2, lymphoid cells are restricted to LILRB1 expression. LILRB1 and LILRB2 are frequently co-expressed with immune-activating LILR family members LILRA1 and LILRA3 in several tumor indications and upregulated in patients non-responsive to T cell checkpoint blockade. Furthermore, the non-classical MHC-I molecule HLA-G, a major ligand of LILRB1 and LILRB2 in the tumor environment, is overexpressed and associated with poor prognosis in multiple solid cancer types. IOMX-0675, a fully human, Fc-silenced, monoclonal immunoglobulin G1 (IgG1) antibody with a highly differentiated binding profile, that binds selectively with high affinity to the inhibitory receptors LILRB1 and LILRB2, while binding only weakly to the closely related immune-activating LILR family members LILRA1 and LILRA3, was identified from iOmx’ proprietary phage display library. A high-resolution Fab-based Octet assay was established to monitor the IOMX-0675-mediated blocking of LILRB1 or LILRB2 binding to HLA-G. The LILRB1/2 cross-specific antibody promotes phagocytic and pro-inflammatory activity of various macrophage subtypes, which was monitored by flow cytometry and cytokine profiling. In co-cultures of monocyte-derived macrophages with autologous T cells, IOMX-0675 shows high potential to reprogram dose-dependently immunosuppressive macrophage, to further activate pro-inflammatory macrophage subtypes and thereby rescues the activity of the lymphoid immune compartment. Even in environments dominated by LILRA1/A3, IOMX-0675 shows a strong binding capacity to the immunosuppressive LILRB1/B2 receptors and significantly repolarizes the immune environment. In summary, we discovered IOMX-0675, a cross-specific antibody antagonizing both LILRB1 and LILRB2 with high selectivity, that exhibits potent reprogramming of the immunosuppressive myeloid compartment and restores cytotoxic T cell activity in the tumor microenvironment. Negligible binding to immune-activating LILR family members by IOMX-0675 could unleash full anti-tumor activity. The differential binding profile of IOMX-0675 provides best-in-class potential and may maximize anti-tumor efficacy for the benefit of patients with high-unmet medical need, who are resistant to T cell checkpoint blockade. Citation Format: Christina Hartl, Jonas Zantow, Ilona-Petra Maser, Marisa Stebegg-Wagner, Simone Friedrich, Jonas Schilz, Stefan Kaden, Ronny Milde, Eugenia Korotkova, Michail Maraslis, Bettina Langer, Michal Swiat, Carmen Ginzel, Carmen Ammerhauser, Lucille Albert, Leonie Majunke, Alina Huth, Kritika Sudan, Murray Yule, Christine Rothe, Hannes Loferer, Maximilian Aigner, Alexander N. Marziale, Stefan Bissinger. IOMX-0675, a LILRB1 and LILRB2 cross-specific antibody, effectively repolarizes immunosuppressive myeloid cells and activates T cells leading to potent tumor cell killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1362.

Single-cell mapping of leukocyte immunoglobulin-like receptors in kidney transplant rejection

Leukocyte immunoglobulin-like receptors (LILRs) are a family of inhibitory or stimulatory receptors expressed by immune cell types belonging to both myeloid and lymphoid lineage. Several members of the LILR family recognize major histocompatibility complex class I and thus play important roles in a range of clinical situations including pregnancy. Moreover, paired immunoglobulin-like receptors (PIRs), the murine orthologs of LILRs, are implicated in experimental transplant allorecognition by monocytes and contribute to the induction of donor-specific monocyte-memory. After non-self recognition, activating PIRs are transiently overexpressed at the surface of monocytes and participate in donor-specific monocyte recruitment, leading to graft rejection in vivo. In the present study, we mapped LILR expression and also their respective reported ligands at single cell level in the renal allograft and circulating cells in the context of kidney transplant rejection. Recipient-derived monocytes were shown to infiltrate the donor tissue and to differentiate into macrophages. We thus also investigate LILR expression during in vitro monocyte-to-macrophage differentiation in order to characterize the myeloid population that directly contribute to allorecognition. Altogether our results emphasize non-classical monocytes and CD68+ M1 macrophages as key players in LILRs-ligand interaction in kidney transplantation.

Plasmodium falciparum RIFIN is a novel ligand for inhibitory immune receptor LILRB2

Plasmodium falciparum causes the most severe form of malaria. Acquired immunity against P. falciparum provides insufficient protection even after repeated infections. Therefore, P. falciparum parasites might exploit inhibitory receptors for immune evasion. P. falciparum RIFINs are products of a multigene family consisting of 150–200 genes. Previously, we demonstrated that some RIFINs downregulate the immune response through the leukocyte immunoglobulin-like receptor (LILR) family inhibitory receptor, LILRB1, and leukocyte-associated immunoglobulin-like receptor 1, LAIR1. In this study, we further analyzed the expression of inhibitory receptor ligands on P. falciparum-infected erythrocytes and found that P. falciparum-infected erythrocytes expressed ligands for another LILR family inhibitory receptor, LILRB2, that recognizes HLA class I molecules as a host ligand. Furthermore, we identified that a specific RIFIN was a ligand for LILRB2 by using a newly developed RIFIN expression library. In addition, the domain 3 of LILRB2 was involved in RIFIN binding, whereas the domains 1 and 2 of LILRB2 were involved in the binding to HLA class I molecules. These results suggest that inhibitory receptor LILRB2 is also targeted by RIFIN for immune evasion of P. falciparum similar to LILRB1 and LAIR1.

TARM1 contributes to development of arthritis by activating dendritic cells through recognition of collagens

TARM1 is a member of the leukocyte immunoglobulin-like receptor family and stimulates macrophages and neutrophils in vitro by associating with FcRγ. However, the function of this molecule in the regulation of the immune system is unclear. Here, we show that Tarm1 expression is elevated in the joints of rheumatoid arthritis mouse models, and the development of collagen-induced arthritis (CIA) is suppressed in Tarm1–/– mice. T cell priming against type 2 collagen is suppressed in Tarm1–/– mice and antigen-presenting ability of GM-CSF-induced dendritic cells (GM-DCs) from Tarm1–/– mouse bone marrow cells is impaired. We show that type 2 collagen is a functional ligand for TARM1 on GM-DCs and promotes DC maturation. Furthermore, soluble TARM1-Fc and TARM1-Flag inhibit DC maturation and administration of TARM1-Fc blocks the progression of CIA in mice. These results indicate that TARM1 is an important stimulating factor of dendritic cell maturation and could be a good target for the treatment of autoimmune diseases.

LILRB3 (ILT5) is a myeloid cell checkpoint that elicits profound immunomodulation.

Despite advances in identifying the key immunoregulatory roles of many of the human leukocyte immunoglobulin-like receptor (LILR) family members, the function of the inhibitory molecule LILRB3 (ILT5, CD85a, LIR3) remains unclear. Studies indicate a predominant myeloid expression; however, high homology within the LILR family and a relative paucity of reagents have hindered progress toward identifying the function of this receptor. To investigate its function and potential immunomodulatory capacity, a panel of LILRB3-specific monoclonal antibodies (mAbs) was generated. LILRB3-specific mAbs bound to discrete epitopes in Ig-like domain 2 or 4. LILRB3 ligation on primary human monocytes by an agonistic mAb resulted in phenotypic and functional changes, leading to potent inhibition of immune responses in vitro, including significant reduction in T cell proliferation. Importantly, agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells. Our findings reveal powerful immunosuppressive functions of LILRB3 and identify it as an important myeloid checkpoint receptor.

Molecular mechanism of the recognition of bacterially cleaved immunoglobulin by the immune regulatory receptor LILRA2

Human leukocyte immunoglobulin-like receptors (LILRs) typically regulate immune activation by binding to the human leukocyte antigen class I molecules. LILRA2, a member of the LILR family, was recently reported to bind to other unique ligands, the bacterially degraded Igs (N-truncated Igs), for the activation of immune cells. Therefore, LILRA2 is currently attracting significant attention as a novel innate immune receptor. However, the detailed recognition mechanisms required for this interaction remain unclear. In this study, using several biophysical techniques, we uncovered the molecular mechanism of N-truncated Ig recognition by LILRA2. Surface plasmon resonance analysis disclosed that LILRA2 specifically binds to N-truncated Ig with weak affinity (Kd = 4.8 μm) and fast kinetics. However, immobilized LILRA2 exhibited a significantly enhanced interaction with N-truncated Ig due to avidity effects. This suggests that cell surface-bound LILRA2 rapidly monitors and identifies bi- or multivalent abnormal N-truncated Igs through specific cross-linking to induce immune activation. Van't Hoff analysis revealed that this interaction is enthalpy-driven, with a small entropy loss, and results from differential scanning calorimetry indicated the instability of the putative LILRA2-binding site, the Fab region of the N-truncated Ig. Atomic force microscopy revealed that N truncation does not cause significant structural changes in Ig. Furthermore, mutagenesis analysis identified the hydrophobic region of LILRA2 domain 2 as the N-truncated Ig-binding site, representing a novel ligand-binding site for the LILR family. These results provide detailed insights into the molecular regulation of LILR-mediated immune responses targeting ligands that have been modified by bacteria.

Structure and flexibility of the extracellular region of the PirB receptor

Murine paired immunoglobulin receptor B (PirB) and its human ortholog leukocyte immunoglobulin-like receptor B2 (LILRB2) are widely expressed inhibitory receptors that interact with a diverse set of extracellular ligands and exert functions ranging from down-regulation of immune responses to inhibition of neuronal growth. However, structural information that could shed light on how PirB interacts with its ligands is lacking. Here, we report crystal structures of the PirB ectodomain; the first full ectodomain structure for a LILR family member, at 3.3-4.5 Å resolution. The structures reveal that PirB's six Ig-like domains are arranged at acute angles, similar to the structures of leukocyte immunoglobulin-like receptor (LILR) and killer-cell immunoglobulin-like receptor (KIR). We observe that this regular arrangement is followed throughout the ectodomain, resulting in an extended zigzag conformation. In two out of the five structures reported here, the repeating zigzag is broken by the first domain that can adopt two alternative orientations. Quantitative binding experiments revealed a 9 μm dissociation constant for PirB-myelin-associated glycoprotein (MAG) ectodomain interactions. Taken together, these structural findings and the observed PirB-MAG interactions are compatible with a model for intercellular signaling in which the PirB extracellular domains, which point away from the cell surface, enable interaction with ligands in trans.

Gp49B is a pathogenic marker for auto-antibody-producing plasma cells in lupus-prone BXSB/Yaa mice.

AbstractImmune homeostasis is critically regulated by the balance between activating and inhibitory receptors expressed on various immune cells such as T and B lymphocytes, and myeloid cells. The inhibitory receptors play a fundamental role in the immune checkpoint pathway, thus maintaining peripheral tolerance. We recently found that expression of leukocyte immunoglobulin-like receptor (LILR)B4, an inhibitory member of the human LILR family, is augmented in auto-antibody-producing plasmablasts/plasma cells of systemic lupus erythematosus (SLE) patients. However, the mechanism behind the 'paradoxical' up-regulation of this inhibitory receptor upon pathogenic antibody-secreting cells is yet to be known. To this end, in this study, we examined if glycoprotein 49B (gp49B), the murine counterpart of human LILRB4, is also elevated in auto-antibody-producing cells in several SLE mouse models, and tried to clarify the underlying mechanism. We found that gp49B is expressed on plasma cells of lupus-prone models but not of healthy C57BL/6 mice, and the level was positively correlated to the anti-double-stranded DNA IgG titer in serum. Gp49B genetic deletion, however, did not abolish the serum auto-antibodies or fully ameliorate the lethal glomerulonephritis, indicating that gp49B is not the sole regulator of lupus but a pathogenic element in the disease. We conclude that the elevated expression of this inhibitory receptor on pathogenic plasma cells was also relevant upon the murine SLE model. The mechanism of gp49B underlying the disease progression in lupus-prone mice has been discussed.

LILRB receptor-mediated regulation of myeloid cell maturation and function.

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.

Leukocyte immunoglobulin-like receptors in human diseases: an overview of their distribution, function, and potential application for immunotherapies.

Myeloid-derived suppressor cells (MDSCs), a population of immature myeloid cells expanded and accumulated in tumor-bearing mice and in patients with cancer, have been shown to mediate immune suppression and to promote tumor progression, thereby, posing a major hurdle to the success of immune-activating cancer therapies. MDSCs, like their healthy counterparts, such as monocytes/macrophages and granulocytes, express an array of costimulatory and coinhibitory molecules as well as myeloid activators and inhibitory receptors, such as leukocyte immunoglobulin-like receptors (LILR) A and B. This review summarizes current findings on the LILR family members in various diseases, their potential roles in the pathogenesis, and possible strategies to revert or enhance the suppressive function of MDSCs for the benefit of patients by targeting LILRs.

Dendritic Cell Immune Responses in HIV-1 Controllers.

Robust HIV-1-specific CD8 T cell responses are currently regarded as the main correlate of immune defense in rare individuals who achieve natural, drug-free control of HIV-1; however, the mechanisms that support evolution of such powerful immune responses are not well understood. Dendritic cells (DCs) are specialized innate immune cells critical for immune recognition, immune regulation, and immune induction, but their possible contribution to HIV-1 immune defense in controllers remains ill-defined. Recent studies suggest that myeloid DCs from controllers have improved abilities to recognize HIV-1 through cytoplasmic immune sensors, resulting in more potent, cell-intrinsic type I interferon secretion in response to viral infection. This innate immune response may facilitate DC-mediated induction of highly potent antiviral HIV-1-specific T cells. Moreover, protective HLA class I isotypes restricting HIV-1-specific CD8 T cells may influence DC function through specific interactions with innate myelomonocytic MHC class I receptors from the leukocyte immunoglobulin-like receptor family. Bi-directional interactions between dendritic cells and HIV-1-specific T cells may contribute to natural HIV-1 immune control, highlighting the importance of a fine-tuned interplay between innate and adaptive immune activities for effective antiviral immune defense.

Leukocyte Ig-Like receptor B1 restrains dendritic cell function through increased expression of the NF-κB regulator ABIN1/TNIP1.

Inhibitory receptors of the human leukocyte immunoglobulin-like receptor family are constitutively expressed on all myeloid cell types and regulate their functional activity. We demonstrate that ligation of the human leukocyte antigen class I-specific receptor LILRB1, during the differentiation of monocytes to dendritic cells in vitro, results in increased expression of the nuclear factor κB inhibitor protein ABIN1 (also known as TNIP1). Similarly increased expression of ABIN1/TNIP1 was observed in the "immunosuppressive" monocyte populations of patients with non-Hodgkin lymphoma ex vivo. Reducing expression of ABIN1/TNIP1 using small interfering ribonucleic acid allows dendritic cells and immunosuppressive monocytes to respond to stimulation by allowing nuclear factor κB translocation to the nucleus (P < 0.001), increasing cell surface expression of antigen presentation and costimulatory molecules (P < 0.01), increasing phagocytic capacity (P < 0.001), secreting proinflammatory cytokines (P < 0.01), and an increasing ability to stimulate T cell responses (P < 0.05). Our study, therefore, identifies an important functional role for ABIN1/TNIP1 in mediating the effects of LILRB1 ligation-induced inhibitory effects on immune responses. Our findings suggest that inhibiting the LILRB1-ABIN1/TNIP1 pathway in antigen-presenting cells could be a therapeutic approach to stimulate antitumor immune responses. Conversely, stimulation of the pathway may also ameliorate autoimmune diseases in which TNIP1 is a susceptibility gene.

The Leukocyte Immunoglobulin-Like Receptor Family Member LILRB5 Binds to HLA-Class I Heavy Chains.

ObjectiveThe leukocyte immunoglobulin-like receptor (LILR) family includes inhibitory and stimulatory members which bind to classical and non-classical HLA-class I. The ligands for many LILR including LILRB5 have not yet been identified.MethodsWe generated C-terminal eGFP and N-terminal FLAG-tagged fusion constructs for monitoring LILR expression. We screened for LILR binding to HLA-class I by tetramer staining of 293T cells transfected with LILRA1, A4, A5 A6 and LILRB2 and LILRB5. We also studied HLA class I tetramer binding to LILRB5 on peripheral monocyte cells. LILRB5 binding to HLA-class I heavy chains was confirmed by co-immunoprecipitation.ResultsHLA-B27 (B27) free heavy chain (FHC) dimer but not other HLA-class I stained LILRB5-transfected 293T cells. B27 dimer binding to LILRB5 was blocked with the class I heavy chain antibody HC10 and anti-LILRB5 antisera. B27 dimers also bound to LILRB5 on peripheral monocytes. HLA-B7 and B27 heavy chains co-immunoprecipitated with LILRB5 in transduced B and rat basophil RBL cell lines.ConclusionsOur findings show that class I free heavy chains are ligands for LILRB5. The unique binding specificity of LILRB5 for HLA-class I heavy chains probably results from differences in the D1 and D2 immunoglobulin-like binding domains which are distinct from other LILR which bind to β2m-associated HLA-class I.

Functional and genetic diversity of leukocyte immunoglobulin-like receptor and implication for disease associations.

Human leukocyte immunoglobulin-like receptors (LILR) are a family of 11 functional genes encoding five activating (LILRA1, 2, 4-6), five inhibitory (LILRB1-5) and one soluble (LILRA3) form. The number of LILR genes is conserved among individuals, except for LILRA3 and LILRA6, which exhibit copy-number variations. The LILR genes are rapidly evolving and showing large interspecies differences, making it difficult to analyze the functions of LILR using an animal model. LILRs are expressed on various cells such as lymphoid and myeloid cells and the expression patterns are different from gene to gene. The LILR gene expression and polymorphisms have been reported to be associated with autoimmune and infectious diseases such as rheumatoid arthritis and cytomegalovirus infection. Although human leukocyte antigen (HLA) class I is a well-characterized ligand for some LILRs, non-HLA ligands have been increasingly identified in recent years. LILRs have diverse functions, including the regulation of inflammation, immune tolerance, cell differentiation and nervous system plasticity. This review focuses on the genetic and functional diversity of the LILR family.

Angiopoietins and angiopoietin-like proteins bind to LILRA/B receptors and activate innate immune responses in human monocytes (INC1P.405)

Abstract Angiopoietins and Angiopoietin-like (ANGPTL) proteins are secreted glycoproteins that play multiple roles in angiogenesis, lipid metabolism, hematopoietic stem cell expansion, and inflammation. Unlike Angiopoietins, which are known to signal through the tyrosine kinase Tie1 or Tie2 receptors, ANGPTL proteins have long been considered orphan ligands. Recently, ANGPTL1, 2, 5, and 7 were shown to bind to human leukocyte immunoglobulin like receptor B2 (LILRB2), resulting in enhancement of human haematopoietic stem cell proliferation and expansion. Leukocyte immunoglobulin-like receptors (LILRs) also named ILTs, LIRs and CD85s, are a family of immunomodulatory molecules that are expressed on professional APCs and regulate their functional properties to influence immune activation and inhibition. While the MHC class I complexes have been identified as the physiological ligands for many LILR members, the direct interaction between LILRs and ANGPTLs has suggested a new signaling mechanism for those two groups of molecules. We have tested Angiopoietins and ANGPTL proteins in binding studies with the LILRA and LILRB family members, and identified additional LILR family members as potential receptors of Angiopoietin-1 and several ANGPTL proteins. We find correlations between these newly described interactions of Angiopoietins and ANGPTL proteins with LILR family members and their abilities to activate innate immune responses in human monocytes.

Copy number and nucleotide variation of the LILR family of myelomonocytic cell activating and inhibitory receptors

Leukocyte immunoglobulin-like receptors (LILR) are cell surface molecules that regulate the activities of myelomonocytic cells through the balance of inhibitory and activation signals. LILR genes are located within the leukocyte receptor complex (LRC) on chromosome 19q13.4 adjacent to KIR genes, which are subject to allelic and copy number variation (CNV). LILRB3 (ILT5) and LILRA6 (ILT8) are highly polymorphic receptors with similar extracellular domains. LILRB3 contains inhibitory ITIM motifs and LILRA6 is coupled to an adaptor with activating ITAM motifs. We analysed the sequences of the extracellular immunoglobulin domain-encoding regions of LILRB3 and LILRA6 in 20 individuals, and determined the copy number of these receptors, in addition to those of other members of the LILR family. We found 41 polymorphic sites within the extracellular domains of LILRB3 and LILRA6. Twenty-four of these sites were common to both receptors. LILRA6, but not LILRB3, exhibited CNV. In 20 out of 48 human cell lines from the International Histocompatibility Working Group, LILRA6 was deleted or duplicated. The only other LILR gene exhibiting genomic aberration was LILRA3, in this case due to a partial deletion.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-013-0742-5) contains supplementary material, which is available to authorized users.

Characterisation of Bovine Leukocyte Ig-like Receptors

Leukocyte Immunoglobulin-like receptors (LILR) are innate immune receptors involved in regulating both innate and adaptive immune functions. LILR show more interspecies conservation than the closely related Killer Ig-like receptors, and homologues have been identified in rodents, primates, seals and chickens. The murine equivalents, paired Ig-like receptors (PIR), contain two additional immunoglobulin domains, but show strong sequence and functional similarities to human LILR. The bovine genome was recently sequenced, with preliminary annotations indicating that LILR were present in this species. We therefore sought to identify and characterize novel LILR within the Bos taurus genome, compare these phylogenetically with LILR from other species and determine whether they were expressed in vivo. Twenty six potential bovine LILR were initially identified using BLAST and BLAT software. Phylogenetic analysis constructed using the neighbour-joining method, incorporating pairwise deletion and confidence limits estimated from 1000 replicates using bootstrapping, indicated that 16 of these represent novel bovine LILR. Protein structures defined using protein BLAST predict that the bovine LILR family comprises seven putative inhibitory, four activating and five soluble receptors. Preliminary expression analysis was performed by mapping the predicted sequences with raw data from total transcript sequence generated using Genome Analyzer IIx (Illumina) to provide evidence that all 16 of these receptors are expressed in vivo. The bovine receptor family appears to contain receptors which resemble the six domain rodent PIR as well as the four domain LILR found in other species.

The emerging role of leukocyte immunoglobulin-like receptors (LILRs) in HIV-1 infection

LILRs represent a group of immunomodulatory molecules that regulate the functional properties of professional APCs and influence immune activation in a variety of disease contexts. Many members of the LILR family recognize peptide/MHC class I complexes as their physiological ligands, and increasing evidence suggests that such interactions are prominently influenced by polymorphisms in HLA class I alleles or sequence variations in the presented antigenic peptides. Emerging data show that LILRs are involved in multiple, different aspects of HIV-1 disease pathogenesis and may critically influence spontaneous HIV-1 disease progression. Here, we review recent progress in understanding the role of LILR during HIV-1 infection by focusing on the dynamic interplay between LILR and HLA class I molecules in determining HIV-1 disease progression, the effects of HIV-1 mutational escape on LILR-mediated immune recognition, the contribution of LILR to HIV-1-associated immune dysfunction, and the unique expression patterns of LILR on circulating myeloid DCs from elite controllers, a small subset of HIV-1-infected patients with natural control of HIV-1 replication. Obtaining a more complete understanding of LILR-mediated immune regulation during HIV-1 infection may ultimately allow for improved strategies to treat or prevent HIV-1-associated disease manifestations.

Dendritic Cell Dysfunction During Primary HIV-1 Infection

Dendritic cells have critical roles for generating and fine-tuning adaptive immune responses and for regulating immune activity through cytokine secretion. In this study, we analyzed functional properties of dendritic cells in primary human immunodeficiency virus type 1 (HIV-1) infection. We found substantial disarray of the functional properties of myeloid and plasmacytoid dendritic cells in acute HIV-1 infection, which included defective antigen-presenting and cytokine secretion properties and was associated with a distinct surface expression profile of immunomodulatory dendritic cell receptors from the leukocyte immunoglobulin-like receptor family. These data indicate that key functional properties of dendritic cells are compromised during primary HIV-1 infection.

An insight into the early mechanisms of allergen-specific immunotherapy

The mechanisms governing the induction of peripheral tolerance as a result of specific immunotherapy are far from being clearly characterized. In the last 15 years, a number of studies have highlighted the tolerogenic role of regulatory T cells, blocking antibodies and anti-inflammatory cytokines such as IL-10 and TGF-β; however, the best part of our knowledge is mostly limited to mechanisms underlying the maintenance phase. By contrast, little is known regarding the very early effects seen in rush and ultrarush immunotherapy protocols. In this article, Bussmann et al. provide evidence on the possible role, first, of inhibitory receptors of the leukocyte immunoglobulin-like receptor family and, second, of the upregulation of indoleamine 2,3-dioxygenase and subsequent tryptophan starvation on the induction of specific tolerance within a few hours after the initial doses. They also suggest that the observed changes reflect the activation of protective mechanisms, which we are just beginning to understand.