European Journal of Immunology
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Interleukin‐15 up‐regulates interleukin‐2 receptor α chain but down‐regulates its own high‐affinity binding sites on human T and B cells Abstract The cytokines interleukin (IL)‐2 and IL‐15 share many biological activities as a consequence of their utilization of the β and γ chains of the IL‐2 receptor. However, each cytokine binds to a specific receptor α chain; IL‐2 with low affinity and IL‐15 with high affinity. Here, we demonstrate that IL‐15, like IL‐2, up‐regulates expression of IL‐2Rα on human T and B cells, but rapidly down‐regulates IL‐15 high‐affinity binding sites, which represent IL‐15Rα. This leads to a decreased responsiveness to IL‐15 as measured by induction of Jak3 tyrosine phosphorylation. These results suggest a mechanism by which IL‐15, a product of activated macrophages, may cooperate with IL‐2 at the initiation of an immune response and enhance subsequent IL‐2 responsiveness during T cell expansion.
European Journal of Immunology - Tập 26 Số 6 - Trang 1235-1239 - 1996
The target tissue in autoimmunity – an influential niche Abstract Central and peripheral tolerance mechanisms were for a long time the only regulatory circuits known in autoimmunity. It is now becoming clear that the target tissue itself may have the capacity to control its own destiny. Here we review mechanisms by which the target tissue regulates local inflammation, and the way this could influence progression to overt autoimmunity. Moreover, we discuss recent data showing that physiological properties of the target tissue can determine the organ specificity of autoimmune disease. These recent discoveries and ideas concerning the regulatory potential of the target tissue may, in the future, add a new dimension to our concept of regulatory circuits in autoimmunity.
European Journal of Immunology - Tập 37 Số 3 - Trang 589-597 - 2007
Programmed death ligand 1 is over‐expressed by neutrophils in the blood of patients with active tuberculosis Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb ), remains one of the world's largest infectious disease problems. Despite decades of intensive study, the immune response to Mtb is incompletely characterised, reflecting the extremely complex interaction between pathogen and host. Pathways that may alter the balance between host protection and pathogenesis are therefore of great interest. One pathway shown to play a role in the pathogenesis of chronic infections, including TB, is the programmed death‐1 (PD‐1) pathway. We show here that the expression of the programmed death ligand 1 (PD‐L1), which interacts with PD‐1, is increased in whole blood from active TB patients compared with whole blood from healthy controls or Mtb ‐exposed individuals, and that expression by neutrophils is largely responsible for this increase.
European Journal of Immunology - Tập 41 Số 7 - Trang 1941-1947 - 2011
Transforming growth factor‐β<sub>1</sub>‐induced expression of the mucosa‐related integrin α<sub>E</sub> on lymphocytes is not associated with mucosa‐specific homing Abstract The integrin αE (HML‐1, αIEL , αM290 ) is largely expressed on lymphocytes in epithelial sites, especially the gut mucosa. We investigated whether αE has any role in homing or delineates a phenotype with distinct migratory behavior. Lymph node T cells were stimulated for 5 days with anti‐CD3 in the presence or absence of transforming growth factor (TGF)‐β1 to generate αE + or αE − cells, respectively. The two populations were then tested for their homing properties in mice. Both αE + (TGF‐β‐treated) and αE − (control) cells of either CD4+ or CD8+ subset had a low capacity to enter the gut and showed the same homing behavior with respect to a variety of other organs. The same was true for αE + and αE − cells that had been briefly stimulated with anti‐CD3 (24 h) and then allowed to return to a resting state before injection, though in this case both populations showed a greater capacity to recirculate through lymphoid tissue than was seen with fully activated cells. The results indicate that αE β7 does not act as a homing receptor, and that the expression of the site‐specific marker αE does not correlate with a distinct homing behavior.
European Journal of Immunology - Tập 25 Số 6 - Trang 1487-1491 - 1995
A new surface antigen on intraepithelial lymphocytes in the intestine Abstract A new surface molecule has been discovered on mouse intestinal intraepithelial lymphocytes (IEL) using a rat anti‐mouse IEL monoclonal antibody, M290. It was expressed at high levels on nearly all IEL and on a majority of T cells in the gut lamina propria. M290 stained, with lower intensity, a small minority of T cells in other lymphoid tissues. Expression was biased towards the CD8+ subset. Stimulation of peripheral T cells with mitogens did not induce expression of the new antigen but addition of transforming growth factor β to stimulated T cells had a marked inductive effect. Sodium dodecyl sulfate‐polyacrylamide gel electrophoretic analysis of IEL surface components precipitated with M290 showed principal bands at 135, 120, 28 and 24 kDa (reduced) and 135, 100, 24 and 21 kDa (nonreduced). Precipitation with antibodies to integrin subunits showed that the new molecular complex was not a member of the β1, β2, or β3 integrin families although all of these were represented on IEL. A 13‐amino acid N‐terminal sequence obtained from the 120‐kDa β subunit of the antigen prepared from an M290+ Thybridoma (MTC‐1) did not show homology with integrins. Pulse‐chase studies using MTC‐1 cells showed that the 135‐kDa α subunit was derived from a 147‐kDa precursor. The function of this new molecular complex is not yet known.
European Journal of Immunology - Tập 20 Số 10 - Trang 2201-2207 - 1990
Recognition of E‐cadherin on epithelial cells by the mucosal T cell integrin α<sub>M290</sub>β7 (αEβ7) Abstract The integrin αM290 β7 on the surface of a T cell hybridoma, MTC‐1, mediated adhesion of these cells to the mouse epithelial cell line CMT93. This interaction was critically dependent on the presence of divalent cations; Mn2+ strongly promoted adhesion, Ca2+ was ineffective and Mg2+ gave intermediate results. Antibodies to molecules on the surface of CMT93 cells were tested for inhibition of adhesion. One monoclonal antibody (mAb) against E‐cadherin, ECCD‐2, was found to have significant inhibitory activity. Other mAb to E‐cadherin and antibodies to other molecules had no effect. To show that inhibition by ECCD‐2 was specific for adhesion mediated by αM290 β7, MTC‐1 cells were induced to adhere to CMT93 via the LFA‐1/ICAM‐1 pathway. For this purpose, the epithelial cells were treated with interferon‐γ and tumor necrosis factor‐α to induce ICAM‐1 expression and, in addition, αM290 β7 on MTC‐1 cells was down‐regulated by culturing the cells in the absence of transforming growth factor β. Under these circumstances adhesion of MTC‐1 cells to CMT93 was inhibited by an antibody to LFA‐1 but not by ECCD‐2. Transfection of mouse L cells with cDNA for mouse E‐cadherin enabled MTC‐1 cells to adhere to them through the αM290 β7 integrin; this interaction was inhibited both by ECCD‐2 and by blocking antibody against the integrin. These data strongly suggest that E‐cadherin is a principal ligand for αM290 β7.
European Journal of Immunology - Tập 25 Số 3 - Trang 852-856 - 1995
A monoclonal antibody (HML‐1) defining a novel membrane molecule present on human intestinal lymphocytes Abstract A monoclonal antibody, HML‐1, was produced by fusion of NSI myeloma cells with spleen cells of a mouse immunized with isolated human intestinal intraepithelial lymphocytes (IEL). Immunofluorescence studies of isolated cells, as well as immunoperoxidase staining of tissue sections, indicated that HML‐1 labeled all the various subsets of human intestinal IEL, approximately 40% of lamina propria T cells, 30% mesenteric lymphoblasts and some lymphocytes in other mucosae, particularly IEL. Conversely, it revealed only rare cells in all other lymphoid compartments. Analysis by polyacrylamide gel gradient electrophoresis showed that HML‐1 precipitated two major noncovalently bound components of approximate mol. masses of 105 and 150 kDa from human IEL. HML‐1 thus defines a novel human membrane antigen present on a subpopulation of lymphocytes preferentially associated with epithelia, and particularly with the intestinal epithelium. The characteristics of this human antigen are very similar to those of an antigen we had previously described in the rat. The possible functional role of this novel class of lymphocyte membrane antigens as well as the nature of the mechanism that triggers their expression remain to be elucidated.
European Journal of Immunology - Tập 17 Số 9 - Trang 1279-1285 - 1987
Expression and regulation of β<sub>7</sub>(βp) integrins on mouse lymphocytes: Relevance to the mucosal immune system Abstract A mouse lymphocyte surface molecule which is selectively expressed by mucosal T cells and detected with the monoclonal antibody (mAb) M290 has provisionally been identified as a β7 integrin. Identification was based on close homology of its β subunit at the N terminus with the recently reported, highly distinctive, human β7 sequence. mAb were prepared against the β and α subunits of the mouse molecule, termed β7 and αM290 , respectively, and used to study surface expression of the two components. β7 was present on most lymph node lymphocytes in association with α4 rather than αM290 . This integrin, β7 α4 , was shown to be identical to LPAM‐1 (βpα4 ) the Peyer's patch homing receptor. Stimulation in vitro of mouse lymph node T cells with anti‐CD3 in the presence of transforming growth factor (TGF)‐β increased β7 expression in about 40% of cells and changed the associated α chain from α4 to the novel αM290 subunit, which, in most cells, was expressed de novo. Immunoprecipitation of β7 both from these cells and from intraepithelial lymphocytes gave closely similar results and showed predominance of the β7 αM290 integrin. It is suggested that in vivo this change in α‐chain usage occurs in mucosal T cells in response to TGF‐β acting in the mucosal microen‐vironment and that the new integrin confers particular adhesive properties, possibly homing specificity, on the cells.
European Journal of Immunology - Tập 21 Số 10 - Trang 2591-2597 - 1991
Anti‐interleukin 2 receptor monoclonal antibodies. Respective role of epitope mapping and monoclonal antibody‐receptor interactions in their antagonist effects on interleukin 2‐dependent T cell growth Abstract Functional studies, using mainly interleukin 2 (IL 2)‐dependent growth of human T cell lines or clones but also mixed lymphocyte cultures and mitogen T cell activation, allowed a collection of locally produced anti‐IL2 receptor monoclonal antibodies (mAb) to be classified. They fell into two groups: one with strong to moderate inhibition of IL2, the other without any detectable functional activity in in vitro assays. Direct and sequential immunoprecipitation as well as peptide mapping confirm that all the mAb recognize the same surface molecule. The parameters responsible for such functional dichotomy were characterized: the main parameter was found to be linked to the epitopic cluster recognized on the molecule by the mAb. All functional mAb pertained to a given epitopic cluster and all the nonfunctional ones to an alternative cluster. Studies on mAb receptor and IL2 receptor interactions confirmed these findings and strongly suggest that functional mAb interact with a region on the IL2 receptor identical or very close to the site of ligand‐receptor interaction. These data could facilitate the choice of mAb to be used in therapeutical approaches in vivo when ethical objections could be overcome by appropriate committees.
European Journal of Immunology - Tập 16 Số 6 - Trang 611-616 - 1986
Fine antigenic variation within H5N1 influenza virus hemagglutinin's antigenic sites defined by yeast cell surface display Abstract Fifteen strains of mAb specific for HA of the A/Hong Kong/482/97 (H5N1) influenza virus were generated. The HA antigenic sites of the human A/Hong Kong/482/97 (H5N1) influenza virus were defined by using yeast cell surface‐displaying system and anti‐H5 HA mAb. Evolution analysis of H5 HA identified residues that exhibit diversifying selection in the antigenic sites and demonstrated surprising differences between residue variation of H5 HA and H3 HA. A conserved neutralizing epitope in the H5 HA protein recognized by mAb H5M9 was found using viruses isolated from 1997–2006. Seven single amino acid substitutions were introduced into the HA antigenic sites, respectively, and the alteration of antigenicity was assessed. The structure obtained by homology‐modeling and molecular dynamic methods showed that a subtle substitution at residue 124 propagates throughout its nearby loop (152–159). We discuss how the structural changes caused by point mutation might explain the altered antigenicity of the HA protein. The results demonstrate the existence of immunodominant positions in the H5 HA protein, alteration of these residues might improve the immunogenicity of vaccine strains.
European Journal of Immunology - Tập 39 Số 12 - Trang 3498-3510 - 2009
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