Preferential Th1 Immune Response in Invariant Chain-Deficient Mice

Topilski, Ian; Harmelin, Alon; Flavell, Richard A.; Levo, Y; Shachar, Idit

doi:10.4049/jimmunol.168.4.1610

Cited by 31 publications

(37 citation statements)

References 58 publications

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“…CD74-KO mice were created almost ten years ago [36], and MIF-KO mice have been developed recently by different targeting strategies [43][44][45][46]. The MIF KO's display strain-dependent variation in immunologic phenotype, but the recent description of an impaired T H 2 response in these mice mimics what has been reported in mice deficient in CD74 [47,48]. CD74-KO mice have developmental abnormalities in their B cell compartment, although Class II expression appears unchanged.…”

Section: How Does the Mif Receptor (Cd74) Explain Mif Action?mentioning

confidence: 79%

Insight into the biology of Macrophage Migration Inhibitory Factor (MIF) revealed by the cloning of its cell surface receptor

Leng

Bucala

2006

Cell Res

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Abbreviations: Alexa-MIF (Alexa-488-modified MIF); ERK-1/2 (extracellular signal-related kinase); KO (gene knock-out); LPS (lipopolysaccharide); MAPK (mitogen-activated protein kinase); MIF (macrophage migration inhibitory factor); RIP (regulated intramembrane proteolysis); sCD74 (soluble CD74 ectodomain); TLR-4 (Toll-like receptor 4). IntroductionThe protein mediator known as macrophage migration inhibitory factor (MIF) is considered to be one of the first cytokines to be discovered. In the late 1950s, "MIF" described an activity elaborated by activated lymphocytes that arrested the random movement of monocytes/macrophages [1]. This activity correlates with delayed-type hypersensitivity in vitro, and it induced significant interest among immunologists for representing a soluble, but non-immunoglobulin, factor that could be studied and manipulated in vitro. By 1966, John David and Barry Bloom independently described that MIF was most likely a protein that was secreted into the conditioned medium of activated lymphocytes [2,3], and immunologists soon measured MIF's eponymous activity by a capillary tube assay. However, MIF was difficult to isolate or clone, so as various other lymphokines (T cell growth factor/IL-2), monokines (endogenous pyrogen/IL-1; tumor necrosis factor/lymphotoxin), and interferons were systematically cloned and produced recombinantly and additional proteins, such as interferon-g and IL-4, were also observed to exhibit migration inhibitory activity, immunologic interest in MIF waned. It wasn't until 1989 that a discrete gene sequence was determined to be associated with MIF [4] and in 1993, pure recombinant protein became available for biologic and structure-function studies [5]. The threedimensional crystal structure of MIF was solved by three laboratories in 1996, thus revealing a new protein fold and structural superfamily with MIF as its defining member [6][7][8]. These studies also provided insights into the likely native form of the protein -a homotrimer with a MW of 37.5 kDa (Figure 1). Figure 1 Three-dimensional ribbon diagram of human MIF, revealing its homotrimeric subunit structure. From ref [7]. Each color denotes one monomer. Human MIF homotrimerCell Research (2006) The recent cloning of MIF receptor fills an important gap in our understanding of the molecular biology and immunology of MIF. The MIF receptor, like MIF, does not fall into any established family of protein mediators, providing both new challenges and opportunities for the structural and functional analysis of MIF signal transduction.

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Section: How Does the Mif Receptor (Cd74) Explain Mif Action?mentioning

confidence: 79%

Insight into the biology of Macrophage Migration Inhibitory Factor (MIF) revealed by the cloning of its cell surface receptor

Leng

Bucala

2006

Cell Res

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“…These transgenic mice have normal Ag presentation and T cell populations but a defect in their B cell differentiation (13,14). Our results suggest that, at least in strains with a poor ability to regulate their autoimmune T cell response (i.e., susceptible strains), B cells have a negative effect on recovery from CNS injury.…”

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confidence: 76%

Severe Immunodeficiency Has Opposite Effects on Neuronal Survival in Glutamate-Susceptible and -Resistant Mice: Adverse Effect of B Cells

Schori

Lantner

Shachar

et al. 2002

The Journal of Immunology

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The resistance of rats or mice to glutamate-induced toxicity depends on their ability to spontaneously manifest a T cell-dependent response to the insult. Survival of retinal ganglion cells (RGCs) exposed to glutamate in BALB/c SCID mice (a strain relatively resistant to glutamate toxicity) was significantly worse than in the wild type. In the susceptible C57BL/6J mouse strain, however, significantly more RGCs survived among SCID mutants than in the matched wild type. RGC survival in the SCID mutants of the two strains was similar. These results suggest 1) that immunodeficiency might be an advantage in strains incapable of spontaneously manifesting protective T cell-dependent immunity and 2) that B cells might be destructive in such cases. After exposure of RGCs to toxic glutamate concentrations in three variants of B cell-deficient C57BL/6J mice, namely muMT−/− (B cell knockout mice) and Ii−/− mice reconstituted with transgenically expressed low levels of Ii p31 isoforms (p31 mice) or Ii p41 isoforms (p41 mice), significantly more RGCs survived in these mice than in the wild type. The improved survival was diminished by replenishment of the B cell-deficient mice with B cells derived from the wild type. It thus seems that B cells have an adverse effect on neuronal recovery after injury, at least in a strain that is unable to spontaneously manifest a T cell-dependent protective mechanism. These findings have clear implications for the design of immune-based therapies for CNS injury.

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“…The MHC class-II invariant chain (CD74) has been shown to be the cell surface receptor for MIF and essential for cell activation under MIF stimulation [47]. Mice deficient in CD74 have a defect on antigen presentation and a reduced Th2 differentiation response with lack of the cardinal features of asthma upon OVA immunization and challenge [48,49]. These effects have also been attributed to impairment on antigen-presentation capacity in the absence of CD74.…”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor is essential for allergic asthma but not for Th2 differentiation

et al. 2007

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Macrophage migration inhibitory factor (MIF) is increased in asthmatic patients and plays a critical role in the pathogenesis of asthma. We show here that mice lacking MIF failed to develop airway hyper-responsiveness (AHR), tissue eosinophilia, and mucus metaplasia. Analysis of the bronchoalveolar fluids revealed a substantial reduction of IL-13, eotaxin and cysteinyl-leukotrienes. The lack of these cardinal features of asthma in MIF -/-mice occurs regardless of high concentrations of IL-4 in the lung and OVAspecific IgE in the serum. Antigen-specific lymphocyte proliferation and IL-13 production were similarly increased in the draining lymph nodes of OVA-immunized and challenged MIF -/-mice compared to WT, but were reduced in the spleen of MIF -/-, thus indicating differential roles of MIF in these compartments. Stimulation of naive CD4 + cells with anti-CD3 antibody demonstrated that MIF -/-cells produced increased amounts of IFN-c and IL-4 compared to WT CD4 + cells. Finally, treatment of sensitized BALB/c mice with neutralizing anti-MIF antibody abrogated the development of ARH and airway inflammation without affecting the production of Th2 cytokines or IgE. The present study demonstrates that MIF is required for allergic inflammation, adding important elements to our knowledge of asthma pathogenesis and suggesting that neutralization of MIF might be of therapeutic value in asthma. IntroductionAllergic asthma is a disorder characterized by chronic lung inflammation, reversible airway obstruction and increases in airway hyper-responsiveness (AHR) to nonspecific stimuli. Several studies have provided compelling evidences that the lung infiltrating leukocytes and the proinflammatory mediators they produce initiate cellular damage, amplify the immune response, cause airway physiological changes and tissue remodeling [1]. The airway inflammation of asthma has a predominance of Th2 CD4 + lymphocytes, eosinophils and mast cells infiltrating the lung interstitium. Several studies indicate the existence of a mechanism dependent on IL-5 and eosinophils that induce pulmonary damage and intensify AHR [3][4][5]. In other studies, however, the induction of AHR was observed despite the absence of infiltrating eosinophils, suggesting dissociation between these phenomena [6][7][8][9][10]. Macrophage migration inhibitory factor (MIF) is a pleiotropic molecule and critical mediator of innate and acquired immune responses [11,12]. Pre-formed MIF protein is present in many cell types and is released in response to different stimuli, such as infection and cytokine stimulation [12]. MIF exhibits several proinflammatory functions, including the induction of TNF-a, IL-1 and NO release from macrophages, and the production of arachidonic acid and eicosanoids through the induction of phospholipase A 2 and cyclooxygenase [13,14]. A unique property of MIF is its secretion by immune cells in response to physiological increase in glucocorticoid levels. Once released, MIF can counterregulate the anti-inflammatory effects of steroids on cyt...

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Preferential Th1 Immune Response in Invariant Chain-Deficient Mice

Cited by 31 publications

References 58 publications

Insight into the biology of Macrophage Migration Inhibitory Factor (MIF) revealed by the cloning of its cell surface receptor

Insight into the biology of Macrophage Migration Inhibitory Factor (MIF) revealed by the cloning of its cell surface receptor

Severe Immunodeficiency Has Opposite Effects on Neuronal Survival in Glutamate-Susceptible and -Resistant Mice: Adverse Effect of B Cells

Macrophage migration inhibitory factor is essential for allergic asthma but not for Th2 differentiation

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