Signal Transduction via MHC Class‐I Molecules in T cells

Tscherning, Thomas; Claësson, Mogens H.

doi:10.1111/j.1365-3083.1994.tb03349.x

Cited by 37 publications

(36 citation statements)

References 44 publications

(9 reference statements)

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“…Several reports have demonstrated that activation induced by cross-linking of HLA class I molecules depends on an association between these molecules and other cell surface proteins such as interleukin-2R or CD3/TCR (45). We further observed that inhibition of cytoskeleton rearrangement by cytochalasin B or D, which may inhibit association of cell surface molecules, prevents HLA class I-but not Fas-mediated apoptosis.…”

Section: Discussionsupporting

confidence: 63%

Caspase-dependent Ceramide Production in Fas- and HLA Class I-mediated Peripheral T Cell Apoptosis

Genestier¹,

Prigent²,

Paillot³

et al. 1998

Journal of Biological Chemistry

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We recently demonstrated that the engagement of HLA class I ␣1 domain induced Fas-independent apoptosis in human T and B lymphocytes. We analyzed the signaling pathway involved in HLA class I-mediated apoptosis in comparison with Fas (APO-1, CD95)-dependent apoptosis. The mouse mAb90 or the rat YTH862 monoclonal antibodies which bind the human HLA class I ␣1 domain induced the production of ceramide which was blocked by addition of the phosphatidylcholine-dependent phospholipase C inhibitor, D609. Furthermore, HLA class I-mediated apoptosis involved at least two different caspases, an interleukin-1 converting enzyme-like protease and another protease inhibited by the CPP32-like protease inhibitor Ac-DEVD-CHO. Despite similarity between Fas and HLA class I signaling pathways, we failed to demonstrate any physical association between these two molecules. We also report that the pan-caspase inhibitory peptide zVADfmk, but not Ac-DEVD-CHO and Ac-YVAD-CHO, inhibited decrease of mitochondrial transmembrane potential and generation of ceramide induced by anti-HLA class I and anti-Fas monoclonal antibodies, whereas all three peptides efficiently inhibited apoptosis. Altogether these results suggest that signaling through Fas and HLA class I involve caspase(s), targeted by zVAD-fmk, which act upstream of ceramide generation and mitochondrial events, whereas interleukin-1 converting enzyme-like and CPP32-like proteases act downstream of the mitochondria.

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Section: Discussionsupporting

confidence: 63%

Caspase-dependent Ceramide Production in Fas- and HLA Class I-mediated Peripheral T Cell Apoptosis

Genestier¹,

Prigent²,

Paillot³

et al. 1998

Journal of Biological Chemistry

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“…Cross-linking of MHC I molecules triggers early (rises in free Ca ϩϩ , tyrosine phosphorylation) and late (cytokine production, increased receptor display, and cell proliferation) responses by T-cells (Tscherning and Claësson, 1994;Bregenholt et al, 1996). The effects of cross-linking may require one or more signaling cascades that involve phosphorylation on the conserved cytoplasmic tyrosine of HLA.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Class I Human Leukocyte Antigen (HLA-I) Molecules with Insulin Receptors and Its Effect on the Insulin-Signaling Cascade

Ramalingam

Chakrabarti

Edidin

1997

MBoC

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Insulin receptor (IR) and class I major histocompatibility complex molecules associate with one another in cell membranes, but the functional consequences of this association are not defined. We found that IR and human class I molecules (HLA-I) associate in liposome membranes and that the affinity of IR for insulin and its tyrosine kinase activity increase as the HLA:IR ratio increases over the range 1:1 to 20:1. The same relationship between HLA:IR and IR function was found in a series of B-LCL cell lines. The association of HLA-I and IR depends upon the presence of free HLA heavy chains. All of the effects noted were reduced or abrogated if liposomes or cells were incubated with excess HLA-I light chain, ␤2-microglobulin. Increasing HLA:IR also enhanced phosphorylation of insulin receptor substrate-1 and the activation of phosphoinositide 3-kinase. HLA-I molecules themselves were phosphorylated on tyrosine and associated with phosphoinositide 3-kinase when B-LCL were stimulated with insulin. INTRODUCTIONThe manifold effects of insulin on cell physiology are mediated by a specific insulin receptor (IR). Insulin binding triggers a conformational change in IR, stimulating its tyrosine kinase activity and leading to its autophosphorylation (Rosen, 1987;White and Kahn, 1994). The insulin signal is propagated downstream of the IR kinase by the binding and tyrosine phosphorylation of docking proteins that connect IR to signaling pathways by mediating the binding of intracellular signaling proteins (Backer et al., 1992;Kuhne et al., 1993;Myers et al., 1994).IR has been shown to associate with other proteins in the plane of the plasma membrane. Some of these associations, i.e., with PC-1, a transmembrane glycoprotein (Maddux et al., 1995) and with ␤ adrenergic receptors (Karoor, et al., 1995;Baltensperger, et al., 1996), clearly have functional consequences. The first affects the kinase activity of IR, and the second affects the function of ␤ adrenergic receptors. In contrast, no functional effects have been clearly shown for another lateral association of IR, i.e., that with the major histocompatibility complex (MHC) I molecules, mouse H2 and human HLA. Although the association of IR with these molecules has been demonstrated using biophysical and biochemical techniques (Fehlmann et al., 1985a;Phillips et al., 1986;Edidin and Reiland, 1990;Liegler et al., 1991), there is little evidence that this association has functional consequences for either IR or MHC I molecules. At best, some studies correlate MHC phenotype with insulin binding and signaling activity (Lafuse and Edidin, 1980;Kittur et al., 1987;Edidin, 1988), but others do not (Verland et al., 1989;Liegler et al., 1991). Thus the consequences, if any, of the association between IR and MHC I molecules remain unclear.We have used a two-part strategy to detect the formation of molecular complexes between IR and human MHC I molecules, HLA, and to measure the functional consequences of this association for insulinmediated signaling and the state of MHC phosphorylati...

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“…Although MHC class I molecules expressed by other cell types such as macrophages, mast cells, fibroblasts, and ECs have been shown to transduce proliferative signals, the intracellular signaling pathways remain to be elucidated (38).…”

mentioning

confidence: 99%

Ligation of HLA Class I Molecules on Endothelial Cells Induces Phosphorylation of Src, Paxillin, and Focal Adhesion Kinase in an Actin-Dependent Manner

Jin¹,

Singh²,

Du³

et al. 2002

The Journal of Immunology

118

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The development of chronic rejection is the major limitation to long-term allograft survival. HLA class I Ags have been implicated to play a role in this process because ligation of class I molecules by anti-HLA Abs stimulates smooth muscle cell and endothelial cell proliferation. In this study, we show that ligation of HLA class I molecules on the surface of human aortic endothelial cells stimulates phosphorylation of Src, focal adhesion kinase, and paxillin. Signaling through class I stimulated Src phosphorylation and mediated fibroblast growth factor receptor (FGFR) translocation to the nucleus. In contrast, Src kinase activity was not involved in class I-mediated transfer of FGFR from cytoplasmic stores to the cell surface. Inhibition of Src protein kinase activity blocked HLA class I-stimulated tyrosine phosphorylation of paxillin and focal adhesion kinase. Furthermore, HLA class I-mediated phosphorylation of the focal adhesion proteins and FGFR expression was inhibited by cytochalasin D and latrunculin A, suggesting a role for the actin cytoskeleton in the signaling process. These findings indicate that anti-HLA Abs have the capacity to transduce activation signals in endothelial cells that may promote the development of chronic rejection.

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Signal Transduction via MHC Class‐I Molecules in T cells

Cited by 37 publications

References 44 publications

Caspase-dependent Ceramide Production in Fas- and HLA Class I-mediated Peripheral T Cell Apoptosis

Caspase-dependent Ceramide Production in Fas- and HLA Class I-mediated Peripheral T Cell Apoptosis

Interaction of Class I Human Leukocyte Antigen (HLA-I) Molecules with Insulin Receptors and Its Effect on the Insulin-Signaling Cascade

Ligation of HLA Class I Molecules on Endothelial Cells Induces Phosphorylation of Src, Paxillin, and Focal Adhesion Kinase in an Actin-Dependent Manner

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