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  1. Top of page
  2. Cover image
  3. A truncated isoform of MR1 activates MAIT cells
  4. Maintaining clonal dominance during persistent CMV infection
  5. Treg cells reverse advanced autoimmune disease but don't eradicate the cause
  6. Recombinant TCRs inhibit MIF – implications for inflammatory diseases
  7. The never-ending quest for models of human allergy
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The cover features a digitally-coloured scanning electron microscopy image of CD37-deficient dendritic cells (DCs) stimulated with lipopolysaccharide. The image is taken from the article by Gartlan et al. (pp. 1208–1219) in which the authors show that DC adherence to fibronectin-coated coverslips is impaired in the absence of the tetraspanin CD37. Gartlan et al. further show that ablation of CD37 in mice also impairs DC migration from skin to draining lymph nodes, chemotactic migration and priming of naive T cells. Together, these findings support a role for CD37 in cellular immunity by promoting DC migration. The added colour is purely for aesthetic purposes and has no biological relevance.

A truncated isoform of MR1 activates MAIT cells

  1. Top of page
  2. Cover image
  3. A truncated isoform of MR1 activates MAIT cells
  4. Maintaining clonal dominance during persistent CMV infection
  5. Treg cells reverse advanced autoimmune disease but don't eradicate the cause
  6. Recombinant TCRs inhibit MIF – implications for inflammatory diseases
  7. The never-ending quest for models of human allergy
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The MR1 (MHC-Related 1) gene encodes MR1A, a monomorphic MHC class I-like protein, which has been shown to present microbial metabolites to a specific T-cell subset known as MAIT (Mucosal-Associated Invariant T) cells. However, the MR1 gene also produces, through differential splicing, two putative truncated isoforms of MR1A, the α3-less transmembrane MR1B and the soluble MR1C. In this issue, Lion et al. demonstrate that MR1B is functionally expressed in transfected cell lines. This isoform is expressed at the cell surface as β2microglobulin-independent, glycosylation-immature homodimers. Importantly, MR1B is able to activate both murine and human MAIT cells to produce cytokines in the presence of bacteria. As the differential splicing of the MR1 gene is highly conserved between species, these findings suggest that these truncated isoforms represent an alternate and/or complementary way for cells to activate MAIT cells in the face of a microbial challenge.

Maintaining clonal dominance during persistent CMV infection

  1. Top of page
  2. Cover image
  3. A truncated isoform of MR1 activates MAIT cells
  4. Maintaining clonal dominance during persistent CMV infection
  5. Treg cells reverse advanced autoimmune disease but don't eradicate the cause
  6. Recombinant TCRs inhibit MIF – implications for inflammatory diseases
  7. The never-ending quest for models of human allergy

Cytomegalovirus (CMV) infections persist for life and drive a dramatic accumulation of virus-specific CD8+ T cells over time. This accumulation, which is called “memory inflation”, is conserved in both mice and humans and results in the largest sustained T-cell populations found in humans. These cells are a critical part of CMV-specific immune surveillance. However their homeostasis is poorly understood. In humans, relatively few T-cell clones with high functional avidity for human (H)CMV tend to comprise the bulk of the population. In this issue, Turula et al. used the murine (M)CMV model and adoptive transfers of OT-I transgenic T cells to demonstrate that MCMV-specific T cells with high functional avidity were not only selected, but also actively suppressed the accumulation of other T cells specific for the same antigen. Thus the relative abundance of individual T-cell clones is determined and maintained in a competitive manner throughout memory inflation.

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Treg cells reverse advanced autoimmune disease but don't eradicate the cause

  1. Top of page
  2. Cover image
  3. A truncated isoform of MR1 activates MAIT cells
  4. Maintaining clonal dominance during persistent CMV infection
  5. Treg cells reverse advanced autoimmune disease but don't eradicate the cause
  6. Recombinant TCRs inhibit MIF – implications for inflammatory diseases
  7. The never-ending quest for models of human allergy
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There is great interest in the possibility of using Treg cells as an immunotherapy for inflammatory diseases. In this issue, Tu et al. examined the effectiveness of Treg cells in reversing autoimmune disease of the stomach and the fate of pathogenic T cells following such treatment in a mouse model of gastritis. A single dose of Treg cells resulted in the repair and restitution of function of stomach tissue that was severely damaged in advanced disease. Treg cells caused depletion or inactivation of autoreactive naïve T cells that were antigen inexperienced, however, autoreactive effector/memory T cells persisted in treated mice, and the persisting autoreactive T cells were able to rapidly cause autoimmune disease if Treg cells were removed. Therefore, Treg cells can suppress pathogenic autoreactive cells in advanced autoimmune disease, reversing tissue damage and improving tissue function. However, the persistence of pathogenic T cells represents a risk for the reoccurrence of disease.

Recombinant TCRs inhibit MIF – implications for inflammatory diseases

  1. Top of page
  2. Cover image
  3. A truncated isoform of MR1 activates MAIT cells
  4. Maintaining clonal dominance during persistent CMV infection
  5. Treg cells reverse advanced autoimmune disease but don't eradicate the cause
  6. Recombinant TCRs inhibit MIF – implications for inflammatory diseases
  7. The never-ending quest for models of human allergy

Macrophage migration inhibitory factor (MIF) was the first cytokine to be discovered more than 40 years ago by Prof. John David. MIF is involved in many inflammatory conditions and is thought to play a major role in the progression of multiple sclerosis (MS). Recombinant TCR ligands (RTLs) comprised of the β1α1 domains of MHC class II linked covalently to an encephalitogenic peptide were developed as a potential immune-therapy for MS. The recent characterization of the RTL receptor on monocytes revealed RTL binding to the MHC class II invariant chain (CD74), which also serves as the MIF receptor. In this issue, Benedek et al. demonstrate that RTLs have a bi-functional role in inhibiting MIF activity in primary mouse cells, not only blocking MIF binding, but also down-regulating CD74 cell-surface expression, thereby inhibiting MIF-induced monocyte survival, cytokine secretion and chemotactic migration. Thus, RTL constitutes a novel MIF inhibitor that may impact MS and other inflammatory diseases.

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The never-ending quest for models of human allergy

  1. Top of page
  2. Cover image
  3. A truncated isoform of MR1 activates MAIT cells
  4. Maintaining clonal dominance during persistent CMV infection
  5. Treg cells reverse advanced autoimmune disease but don't eradicate the cause
  6. Recombinant TCRs inhibit MIF – implications for inflammatory diseases
  7. The never-ending quest for models of human allergy
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Human allergy is a debilitating disease in developed countries. Allergic symptoms range from hayfever, dermatitis and asthma to life-threatening anaphylaxis. Although decades of research have shown that chronic inflammation driven by B cells and allergen-specific immunoglobulin is at the core of the disease, we still lack an in-depth understanding of the regulatory mechanisms involved. Furthermore, we still lack good experimental models which faithfully mimic human allergy. In this issue, Lübben et al. generated an IgE over-expressing mouse by knocking-in IgE into the IgG1 gene locus. This model allows the in vivo analysis of elevated polyclonal antigen-specific IgE responses, suggesting that IgE is the most potent immunoglobulin in active experimental systemic anaphylaxis. That basophils might be the main mediators of IgE-mediated anaphylaxis adds to an on-going scientific controversy regarding the role of mast cells vs. basophils, and IgG vs. IgE, in acute allergic reactions.