Identification of a murine Peyer's patch—specific lymphocyte homing receptor as an integrin molecule with an α chain homologous to human VLA-4α

Holzmann, Bernhard; McIntyre, Bradley W.; Weissman, Irving L.

doi:10.1016/0092-8674(89)90981-1

Cited by 459 publications

(209 citation statements)

References 34 publications

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“…Only the surviving SP cells upregulated the tissue-homing receptors for LNs [L-selectin, CD62L (57)] and for PP HEVs [integrin α 4 β 7 (58,59)]. During these studies my fellows and I had discovered the homing receptors (59)(60)(61)(62)(63)(64)(65)(66)(67) and the essential regions of lymphoid organs by finding out how to stain tissue sections for cell membrane antigens (31 chains (68)(69)(70). The timing of IgH chain rearrangement occurred in distinct pro-B dividing cells, which was prior to light chain rearrangement in nondividing pre-B cells (68,71).…”

Section: The Thymus Thymic Maturation B Lymphocyte Development Hommentioning

confidence: 99%

How One Thing Led to Another

Weissman

2016

Annu. Rev. Immunol.

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I started research in high school, experimenting on immunological tolerance to transplantation antigens. This led to studies of the thymus as the site of maturation of T cells, which led to the discovery, isolation, and clinical transplantation of purified hematopoietic stem cells (HSCs). The induction of immune tolerance with HSCs has led to isolation of other tissue-specific stem cells for regenerative medicine. Our studies of circulating competing germline stem cells in colonial protochordates led us to document competing HSCs. In human acute myelogenous leukemia we showed that all preleukemic mutations occur in HSCs, and determined their order; the final mutations occur in a multipotent progenitor derived from the preleukemic HSC clone. With these, we discovered that CD47 is an upregulated gene in all human cancers and is a “don't eat me” signal; blocking it with antibodies leads to cancer cell phagocytosis. CD47 is the first known gene common to all cancers and is a target for cancer immunotherapy.

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Section: The Thymus Thymic Maturation B Lymphocyte Development Hommentioning

confidence: 99%

How One Thing Led to Another

Weissman

2016

Annu. Rev. Immunol.

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“…The murine bend3 endothelioma cell line was kindly provided by Dr. W. Risau (Bad Nauheim, FRG) and was maintained in DMEM with high glucose (Life Technologies, Eggenstein, FRG) containing 10% low endotoxin fetal bovine serum (FBS) (Life Technologies). Cells were activated with LPS from Salmonella enteritidis (Sigma, Deisenhofen, FRG) at a dose of 1 #g/ml for 4 h at 37~ The T cell lymphoma line TK-1 (13,27), the lymphoma cell lines ESb 289 and Eb (28), and the B lymphoma line L1-2 were maintained in RPMI 1640 medium supplemented with 10% FBS, 2 mM L-glutamine, 10 mM Hepes, and 50 mM 2-ME (culture medium). The T cell hybridoma cell line BI 141 (29) was kindly provided by A. Reske-Kunz (University of Mainz, Mainz, FRG) and was maintained in Iscove's medium supplemented with 5% FBS, sodium pyruvate, and 50 mM 2-ME.…”

Section: Methodsmentioning

confidence: 99%

“…The 150-kD band represents the intact a4 chain and the smaller bands are proteolytic cleavage fragments of the a4 chain that exist in the membrane (44,45). A/3 chain is not visible under the solubilisation conditions since in the mouse, the cx4/3 heterodimers are not stable in the absence of Ca 2+ and Mg z+ ions (13,46). Treatment of the precipitate with endoglycosidase F (Endo F) to remove N-linked glycans decreased the apparent mass of the bands to 92, 60, and 50 kD, respectively (lane 2).…”

Section: Frg)mentioning

confidence: 99%

The alpha 4 integrin chain is a ligand for alpha 4 beta 7 and alpha 4 beta 1.

Altevogt

Hubbe

Ruppert

et al. 1995

The Journal of Experimental Medicine

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SummaryThe heterodimeric ol4 integrins c~4~7 lymphocyte Peyer's patch adhesion molecule ([LPAM]-I) and ol431 (very late antigen-4) are cell surface adhesion molecules involved in lymphocyte trafficking and lymphocyte-cell and matrix interactions. Known cellular ligands include vascular cell adhesion molecule (VCAM)-I, which binds to ~431 and ol437, and the mucosal addressin cell adhesion molecule (MAdCAM)-I, which binds to ol437. Here we show that the o~4 chain of these integrins can itself serve as a ligand. The c~4 chain, immunoaffinity purified and immobilized on glass slides, binds thymocytes and T lymphocytes. Binding exhibits divalent cation requirements and temperature sensitivity which are characteristic of integrin-mediated interactions, and is specifically inhibited by anti-cx4 integrin antibodies, which exert their effect at the cell surface. Cells expressing exclusively c~4/~7 (TK-1) or c~431 (L1-2) both bound avidly, whereas ol4-negative cells did not. A soluble 34-kD ol4 chain fragment retained binding activity, and it inhibited lymphocyte adhesion to ~4 ligands. It has been shown that c~4 integrin binding to fibronectin involves an leucine-aspartic acid-valine (LDV) motif in the HeplI/IIICS region of fibronectin (CS-1 peptide), and homologous sequences are important in binding to VCAM-1 and MAdCAM-1. Three conserved LDV motifs occur in the extracellular sequence of c~4. A synthetic LDV-containing c~4-derived oligopeptide supports c~4-integrin-dependent lymphocyte adhesion and blocks binding to the 34-kD ol4 chain fragment. Our results suggest that r and r integrins may be able to bind to the ol4 subunit on adjacent cells, providing a novel mechanism for ol4 integrin-mediated and activation-regulated lymphocyte interactions during immune responses.

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“…These donor T cells home, as do all T cells, to lymphoid organs (23,24), and there they carry out destructive graft-vs.-host reactions, compromising or eliminating these tissues wherein immune responses to exogenous antigens take place. In addition, mature donor T cells expand in response to minor antigens present at a high frequency at the time of transplantation (25,26), and thereby suppress the production of naive T cells by rapidly saturating the lymphocyte pool (27)(28)(29).…”

Section: Hsc Grafts Enhance Lymphoid Reconstitution and De Novo Regenmentioning

confidence: 99%

Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity

Müller

Shashidhar

Küpper

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life-threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8 + memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen-specific cells while allowing the reconstitution of a naive T-cell pool.

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Identification of a murine Peyer's patch—specific lymphocyte homing receptor as an integrin molecule with an α chain homologous to human VLA-4α

Cited by 459 publications

References 34 publications

How One Thing Led to Another

How One Thing Led to Another

The alpha 4 integrin chain is a ligand for alpha 4 beta 7 and alpha 4 beta 1.

Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity

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