TAP transcription and phosphatidylinositol linkage mutants are defective in activation through the T cell receptor

The plasma membrane is compartmentalized into microdomains and the association/dissociation of receptors and signaling molecules with/from these membrane domains is a major principle for regulation of signal transduction. By following the reorganization of microdomains on living cells and performing biochemical studies, we show that Ab targeting of the T cell activation-associated Ag CD147 prevents TCR stimulation-dependent reorganization and clustering of microdomains. Triggering CD147 induces a displacement of the GPI-anchored coreceptors CD48 and CD59 from microdomains in human T lymphocytes. This perturbation of microdomains is accompanied by a selective inhibition of TCR-mediated T cell proliferation. The CD147-inhibited cells secret normal levels of IL-2 but acquire reduced amounts of the IL-2 receptor α-chain CD25. These results indicate that negative regulating signals can modulate microdomains and suggest a general mechanism for inhibition of receptor signaling.

Section: Discussionsupporting

confidence: 76%

Selective Inhibition of T Cell Activation Via CD147 Through Novel Modulation of Lipid Rafts

Staffler

Szekeres

Schütz

et al. 2003

“…This later possibility is consistent with signaling property of Ly-6 proteins (2, 3). A body of data on cell lines suggests that TCR stimulation is impaired in T cell hybridomas that have lost Ly-6A.2 expression due to mutations (34). Other experiments with normal T cells or T cell clones, in which Ly-6A.2 expression was extinguished by either antisense oligonucleotides (35) or Ly-6A.2 cDNA (36), respectively, support these findings.…”

Section: Cd8supporting

confidence: 62%

A Monoclonal Antibody Against the 66-kDa Protein Expressed in Mouse Spleen and Thymus Inhibits Ly-6A.2-Dependent Cell-Cell Adhesion

English

Kosoy

Pawlinski

et al. 2000

Self Cite

The Ly-6 locus encodes several cell surface proteins of 10–12 kDa. Some members of this multigene family may function in cell signaling and/or cell adhesion processes. T lymphocytes overexpressing Ly-6A.2 (one member of the Ly-6 gene family) protein homotypically aggregate when cultured in vitro. Further analysis of this homotypic aggregation suggests that Ly-6A.2 participates in cell-cell adhesion. These observations indicated the presence of a Ly-6 ligand(s) on the surface of lymphoid cells. In this study we report generation of a hamster mAb, 9AB2, that blocks Ly-6A.2-dependent cell-cell adhesion. The 9AB2 Ab recognizes a 66-kDa glycoprotein with unique tissue expression. The 9AB2 mAb does not bind Ly-6A.2, but coimmunoprecipitates Ly-6A.2 molecule. Moreover, 9AB2 Ag-expressing thymocytes specifically bind to Chinese hamster ovary cells overexpressing Ly-6A.2 protein, and this binding is specifically blocked by 9AB2 and anti-Ly-6A.2 Abs. These results suggest that the 66-kDa protein recognized by 9AB2 mAb is the putative ligand for Ly-6A.2.

“…Published reports have suggested role of Ly-6 protein in T cell signaling (32,33) and cell adhesion (34 -36). Surface expression of Ly-6A.2 is important for immunoresponsiveness of both T-T hybridomas (37) and normal T cells (38). Interestingly, surface expression of TCR/CD3 expression on T-T hybridomas is important for stimulation through the Ly-6 protein (39,40).…”

mentioning

confidence: 99%

Ly-6A.2 Expression Regulates Antigen-Specific CD4+ T Cell Proliferation and Cytokine Production

Henderson

Kamdar

Bamezai

2002

Self Cite

Ly-6 proteins appear to serve cell adhesion and cell signaling function, but the precise role of Ly-6A.2 in CD4+ T lymphocytes is still unclear. Overexpression of Ly-6A.2 in T lymphocytes has allowed us to analyze the influence of elevated Ly-6A.2 expression on T cell function. In this study we report reduced proliferation of CD4+ T cells overexpressing Ly-6A.2 in response to a peptide Ag. Moreover, the Ly-6A.2-overexpressing CD4+ cells generated elevated levels of IL-4, a key factor that propels the differentiation of naive CD4+ T cells into Th2 subset. The hyporesponsiveness of Ly-6A.2 transgenic CD4+ T cells is dependent on the interaction of Ly-6A.2 T cells with the APCs and can be reversed by blocking the interaction between Ly-6A.2 and a recently reported candidate ligand. Overexpression of Ly-6A.2 in CD4+ T cells reduced their Ca2+ responses to TCR stimulation, therefore suggesting effects of Ly-6A.2 signaling on membrane proximal activation events. In contrast to the observed Ag-specific hyporesponsiveness, the Ly-6A.2 transgenic CD4+ T cells produced IL-4 independent of the interactions between Ly-6A.2 and the candidate Ly-6A.2 ligand. Our results suggest that 1) interaction of Ly-6A.2 with a candidate ligand regulates clonal expansion of CD4+ Th cells in response to an Ag (these results also provide further functional evidence for presence of Ly-6A.2 ligand on APC); and 2) Ly-6A.2 expression on CD4+ T cells promotes production of IL-4, a Th2 differentiation factor.