Signal transduction in lymphocyte activation through crosslinking of HLA class I molecules

Gilliland, Lisa K.; Norris, Nancy; Grosmaire, Laura S.; Ferrone, Soldano; Gladstone, Paul; Ledbetter, Jeffrey A.

doi:10.1016/0198-8859(89)90089-x

Cited by 48 publications

(21 citation statements)

References 46 publications

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“…We have recently described the association of CD82 with MHC class I [6]. Indeed MHC class I ligands (soluble or CD8-transfected cells, [41]) or anti-MHC class I mAb [42], have been shown also to deliver co-stimulatory signals to T lymphocytes. However, MHC class I engagement was reported to involve a p56lck activation pathway [43] and did not lead to sustained alteration of cellular morphology.…”

Section: Discussionmentioning

confidence: 99%

Signaling through the tetraspanin CD82 triggers its association with the cytoskeleton leading to sustained morphological changes and T cell activation

et al. 1998

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In this report, we provide new evidence of a crosstalk between T cell activation and adhesion processes through a functional cytokeleton. We show that CD82 signaling induces long-lasting adhesion, spreading and development of membrane extensions, involving actin polymerization. Addition of various co-stimuli (phorbol 12-myristate 13-acetate or monoclonal antibodies to CD3 or CD2) increases the CD82-induced morphological alterations and, reciprocally, CD82 engagement synergizes with these stimuli to induce T cell activation as indicated by both primary tyrosine phosphorylation and IL-2 production. Different kinases are involved in both processes. CD82 co-signaling involves src kinases including p56 Ick. On the other hand, the CD82-induced alterations of cell morphology are negatively regulated by cAMP-dependent kinases independently of activation of src kinases. Simultaneously with cytoskeletal rearrangements, we observed an inducible association of CD82 with the cytoskeletal matrix. In addition, the potentiating and stabilizing effects induced by CD82 cross-linking on tyrosine phosphorylation were abolished by cytoskeleton-disrupting agents. These results suggest that the actin polymerization triggered by CD82, through its ability to associate with the cytoskeletal matrix, is the primary step involved in the CD82 induced co-stimulatory activity. Our data provide further evidence for a direct role of the actin cytoskeleton as a major component for sustained signal transduction in T cells and suggest that tetraspanins could be "membrane organizers" connecting both surface and intracellular molecules.

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Section: Discussionmentioning

confidence: 99%

Signaling through the tetraspanin CD82 triggers its association with the cytoskeleton leading to sustained morphological changes and T cell activation

et al. 1998

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“…6 B, C, E). Since double cross-linking of class I has been shown to trigger Ca2+ increases [20], cells expressing Mu/H-2 receptors were treated with a biotin-coupled goat F(ab')z anti-p followed by avidin. Panels C and E (Fig.…”

Section: Calcium Studiesmentioning

confidence: 99%

“…The rate of endocytosis of the MHC class I-antibody complexes is also much slower than that of cross-linked surface IgM [19]. Finally, under normal conditions, cross-linking of class I has no effect on the intracellular calcium concentration as seen in response to cross-linking of mIgM [20].…”

Section: Introductionmentioning

confidence: 99%

Role of the transmembrane and cytoplasmic domains of surface IgM in endocytosis and signal transduction

et al. 1992

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The cross-linking of membrane IgM (mIgM) triggers the activation and differentiation of B lymphocytes. One very rapid result of the cross-linking is the activation of phospholipase C, the subsequent mobilization of free calcium from internal stores and the activation of protein kinase C. This is followed by a redistribution of the receptor-ligand complexes to a small cap on the B cell surface, the first step in endocytosis and antigen processing. Cross-linking of major histocompatibility complex (MHC) class I neither stimulates the release of intracellular calcium nor does it induce capping and endocytosis of the cell surface receptors. In this study, we sought to determine the role of the two carboxyterminal domains of the mu heavy chain in signal transduction, capping and endocytosis of mIgM. We took advantage of the clear differences between MHC class I molecules and mIgM, replacing the transmembrane and cytoplasmic domains of mu by their MHC class I equivalents. Our results show that the hybrid heavy chain could still associate with light chains and assemble into a tetramer on the cell surface. However, cross-linking of the hybrid cell receptor produced neither release of calcium from internal stores, nor capping and endocytosis. These observations demonstrate that the two carboxy-terminal domains of mu are critical to both signal transduction and modulation of the mIgM-ligand complexes from the surface of B lymphocytes.

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“…Furthermore, it has been shown that both inhibition and activation can be regulated by the degree of aggregation of membrane-bound HLA class I molecules. Thus, while crosslinking of mAb specific for polymorphic HLA-A and HLA-B, or monomorphic determinants increases their inhibition of PHA-induced proliferation, aggregation of HLA class I molecules enhances proliferation of PBMC in the presence of sub-mitogenic doses of polymorphonuclear antigens (PMA) (11). Therefore, it is possible that the degree of HLA class I aggregation and the use of different T cell activation pathways may account for the observed individual variation in the suppression mediated by anti-HLA class I mAbs.…”

Section: Discussionmentioning

confidence: 99%

Regulation of T cell response to leishmania antigens by determinants of histocompatibility leukocyte class I and II molecules

Bacellar

Russo

Carvalho

1998

Braz J Med Biol Res

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It has been shown that HLA class I molecules play a significant role in the regulation of the proliferation of T cells activated by mitogens and antigens. We evaluated the ability of mAb to a framework determinant of HLA class I molecules to regulate T cell proliferation and interferon gamma (IFN-γ) production against leishmania, PPD, C. albicans and tetanus toxoid antigens in patients with tegumentary leishmaniasis and healthy subjects. The anti-major histocompatibility complex (MHC) mAb (W6/32) suppressed lymphocyte proliferation by 90% in cultures stimulated with αCD3, but the suppression was variable in cultures stimulated with leishmania antigen. This suppression ranged from 30-67% and was observed only in 5 of 11 patients. IFN-γ production against leishmania antigen was also suppressed by anti-HLA class I mAb. In 3 patients IFN-γ levels were suppressed by more than 60%, while in the other 2 cultures IFN-γ levels were 36 and 10% lower than controls. The suppression by HLA class I mAb to the proliferative response in leishmaniasis patients and in healthy controls varied with the antigens and the patients or donors tested. To determine whether the suppression is directed at antigen presenting cells (APCs) or at the responding T cells, experiments with antigen-primed non-adherent cells, separately incubated with W6/32, were performed. Suppression of proliferation was only observed when the W6/32 mAb was added in the presence of T cells. These data provide evidence that a mAb directed at HLA class I framework determinants can suppress proliferation and cytokine secretion in response to several antigens.

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Signal transduction in lymphocyte activation through crosslinking of HLA class I molecules

Cited by 48 publications

References 46 publications

Signaling through the tetraspanin CD82 triggers its association with the cytoskeleton leading to sustained morphological changes and T cell activation

Signaling through the tetraspanin CD82 triggers its association with the cytoskeleton leading to sustained morphological changes and T cell activation

Role of the transmembrane and cytoplasmic domains of surface IgM in endocytosis and signal transduction

Regulation of T cell response to leishmania antigens by determinants of histocompatibility leukocyte class I and II molecules

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