Trilineage Sequencing Reveals Complex TCRβ Transcriptomes in Neutrophils and Monocytes Alongside T Cells.

Recent findings indicate the presence of T cell receptor (TCR)-based combinatorial immune receptors beyond T cells in neutrophils and monocytes/macrophages. In this study, using a semiquantitative trilineage immune repertoire sequencing approach as well as under rigorous bioinformatic conditions, we identify highly complex TCRβ transcriptomes in human circulating monocytes and neutrophils that separately encode repertoire diversities one and two orders of magnitude smaller than that of T cells. Intraindividual transcriptomic analyses reveal that neutrophils, monocytes, and T cells express distinct TCRβ repertoires with less than 0.

Immediate Neutrophil-Variable-T Cell Receptor Host Response in Bacterial Meningitis.

Bacterial meningitis is a life-threatening disease that evokes an intense neutrophil-dominated host response to microbes invading the subarachnoid space. Recent evidence indicates the existence of combinatorial V(D)J immune receptors in neutrophils that are based on the T cell receptor (TCR). Here, we investigated expression of the novel neutrophil TCRαβ-based V(D)J receptors in cerebrospinal fluid (CSF) from human patients with acute-phase bacterial meningitis using immunocytochemical, genetic immunoprofiling, cell biological, and mass spectrometric techniques.

Expression of combinatorial immunoglobulins in macrophages in the tumor microenvironment.

Recent evidence indicates the presence of macrophage subpopulations that express the TCRαβ in chronic inflammatory diseases such as tuberculosis and atherosclerosis and in the tumor microenvironment. Here, we demonstrate that a second subpopulation of macrophages expresses rearranged heavy and light chain immunoglobulins. We identify immunoglobulin expression in human and murine monocytes, in ex vivo differentiated macrophages and macrophages from the tumor microenvironment of five randomly selected distinct human tumor entities.

The macrophage-TCRαβ is a cholesterol-responsive combinatorial immune receptor and implicated in atherosclerosis.

Recent evidence indicates constitutive expression of a recombinatorial TCRαβ immune receptor in mammalian monocytes and macrophages. Here, we demonstrate in vitro that macrophage-TCRβ repertoires are modulated by atherogenic low density cholesterol (LDL) and high-density cholesterol (HDL). In vivo, analysis of freshly obtained artery specimens from patients with severe carotid atherosclerosis reveals massive abundance of TCRαβ(+) macrophages within the atherosclerotic lesions.

A second combinatorial immune receptor in monocytes/macrophages is based on the TCRγδ.

Recent evidence indicates that monocytes and macrophages express T cell receptor (TCR)αβ-like combinatorial immune receptors. Here, we demonstrate the presence of a second recombinatorial immunoreceptor, which is structurally based on the TCR γ- and δ-chains, in human and murine monocytes and differentially activated macrophages (referred to here as TCRL(m)γδ). In vitro, infection of macrophages with mycobacteria and gram positive or gram negative bacteria induced expression of donor-specific and differential TCRL(m)Vδ repertoires indicating that the novel immunoreceptor represents a dynamic flexible host defense system that responds to bacterial challenge.

Extralymphocytic flexible immune recognition: a new angle on inflammation and aging.

Longstanding immunological dogma holds that flexible immune recognition, which forms the mechanistic basis of adaptive immunity, is strictly confined to the lymphocyte lineage. In higher vertebrates, flexible immune recognition is represented by recombinatorial antigen receptors of enormous diversity known as immunoglobulins, expressed by B lymphocytes, and the T cell receptor (TCR), expressed by T lymphocytes. The recent discovery of recombinatorial immune receptors that are structurally based on the TCR (referred to as TCR-like immunoreceptors, "TCRL") in myeloid phagocytes such as neutrophils and monocytes/macrophages now challenges the lymphocentric paradigm of flexible immunity.

On the horizon: flexible immune recognition outside lymphocytes.

Since decades there is consensus among immunologists that in jawless and jawed vertebrates flexible immune recognition is strictly confined to the lymphoid lineage. In jawed vertebrates the adaptive immune system is represented by two lineages of lymphocytes, B cells and T cells that express recombinatorial antigen receptors of enormous diversity known as immunoglobulins and the T cell receptor (TCR). The recent identification of recombined immune receptors that are structurally based on the TCR in subpopulations of neutrophils and eosinophils (referred to here as TCR-like immunoreceptors, "TCRL") provides unexpected evidence for the existence of flexible host defense mechanisms beyond the realm of lymphocytes.

The neutrophil recombinatorial TCR-like immune receptor is expressed across the entire human life span but repertoire diversity declines in old age.

Recent evidence has revealed the existence of T cell receptor (TCR) αβ-based recombinatorial immune receptors in phagocytes. Here, we performed a systematic survey of the variable β-chain repertoires of the neutrophil TCR-like αβ immunoreceptor (referred to as TCRL(n)αβ) in defined cohorts of young and old individuals. Peripheral blood CD15(+) neutrophils from young adults (age 30 ± 7 years, n=12) expressed an average number of 13 ± 6 distinct TCRL(n) Vβ-chains from the total pool of 25 human Vβ-chains.

A TNF-regulated recombinatorial macrophage immune receptor implicated in granuloma formation in tuberculosis.

Macrophages play a central role in host defense against mycobacterial infection and anti- TNF therapy is associated with granuloma disorganization and reactivation of tuberculosis in humans. Here, we provide evidence for the presence of a T cell receptor (TCR) αβ based recombinatorial immune receptor in subpopulations of human and mouse monocytes and macrophages. In vitro, we find that the macrophage-TCRαβ induces the release of CCL2 and modulates phagocytosis.

A variable immunoreceptor in a subpopulation of human neutrophils.

Neutrophils are thought to rely solely on nonspecific immune mechanisms. Here we provide molecular biological, immunological, ultrastructural, and functional evidence for the presence of a T cell receptor (TCR)-based variable immunoreceptor in a 5-8% subpopulation of human neutrophils. We demonstrate that these peripheral blood neutrophils express variable and individual-specific TCRalphabeta repertoires and the RAG1/RAG2 recombinase complex.

Benefit of Kupffer cell modulation with glycine versus Kupffer cell depletion after liver transplantation in the rat: effects on postischemic reperfusion injury, apoptotic cell death graft regeneration and survival.

Inhibition or destruction of Kupffer cells (KC) may protect against ischemia-reperfusion (IR) induced primary graft nonfunction (PNF) in liver transplantation. Besides KC activation, PNF is characterized by microvascular perfusion failure, intrahepatic leukocyte accumulation, cell death and hepatocellular dysfunction. KCs can be inactivated by different agents including gadolinium chloride (GdCl3), methyl palmitate (MP) and glycine.