LFA-1 Regulates CD8+ T Cell Activation via T Cell Receptor-mediated and LFA-1-mediated Erk1/2 Signal Pathways

Abstract

LFA-1 regulates T cell activation and signal transduction through the immunological synapse. T cell receptor (TCR) stimulation rapidly activates LFA-1, which provides unique LFA-1-dependent signals to promote T cell activation. However, the detailed molecular pathways that regulate these processes and the precise mechanism by which LFA-1 contributes to TCR activation remain unclear. We found LFA-1 directly participates in Erk1/2 signaling upon TCR stimulation in CD8؉ T cells. The presence of LFA-1, not ligand binding, is required for the TCR-mediated Erk1/2 signal pathway. LFA-1-deficient T cells have defects in sustained Erk1

Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression

“…In contrast, HBZ-specific CTLs did not kill a significant number of Tax-expressing cells; nor was any reduction in Tax MFI observed. We conclude that presentation of HBZ [26][27][28][29][30][31][32][33][34] by naturally-infected cells from HLA-A*A02 + individuals was not sufficient to efficiently trigger cytolytic functions at this E:T ratio. 7.…”

“…In the virological synapse, the interaction of LFA-1 on uninfected cells with ICAM-1 on Tax + infected cells induces cytoskeletal rearrangement and directional assembly and budding of viral particles [25,26]; the ICAM-1-LFA-1 interaction may also explain why HTLV-1-specific CTLs are preferentially infected with HTLV-1 [27]. In the immunological synapse, LFA-1 ligation enhances signalling from the T cell receptor in CD8+ T cells [28,29] lowering the activation threshold for effector functions. Since the absolute number of peptide-HLA complexes and the stability of the immunological Figure 5 HBZ-1 efficiently recognises both naturally processed and exogenously loaded HBZ 26-34. (A) HBZ-1 detects its cognate epitope with greater sensitivity than Tax-1.…”

“…After co-incubation with either HBZ-specific or Tax-specific CTLs, there was a significant reduction in the median intensity of HLA-A*02 expression by Tax + CD4 + cells ( Figure 6C). In contrast, the level of HLA-A*02 expression was unchanged on Tax We hypothesized that Tax [11][12][13][14][15][16][17][18][19] could inhibit presentation of HBZ [26][27][28][29][30][31][32][33][34] by competing for binding to HLA-A*0201 ( Figure 7A). At saturating concentrations of HBZ 26-34 (2 uM), preincubation with Tax 11-19 had no effect on lysis of BLCL by CTLs.…”

“…However, when the concentration of HBZ [26][27][28][29][30][31][32][33][34] was limiting (0.02-0.2 uM), Tax [11][12][13][14][15][16][17][18][19] could inhibit CTL detection of HBZ, but only when present in 10,000-fold molar excess. We also quantified the frequency of CD8 + T cells specific for the Tax [11][12][13][14][15][16][17][18][19] and HBZ [26][27][28][29][30][31][32][33][34] epitopes in each of the donors in this study. IFN-γ-producing Tax [11][12][13][14][15][16][17][18][19] specific CD8 + cells were observed in all individuals, whereas no HBZ 26-34 specific CD8 + cells were detected ( Figure 7B).…”

“…Therefore, any observed reduction in the rate of killing of naturally-infected cells by the HBZ-specific clone was due to the level of epitope processing or presentation by target cells, rather than lower CTL efficiency. To confirm that the HBZ [26][27][28][29][30][31][32][33][34] epitope is processed and presented naturally, we transfected cells with an expression plasmid encoding fulllength HBZ (HBZ-IRES-GFP) or GFP alone [13]: HBZ-transfected cells were selectively killed by HBZ-1 CTLs ( Figure 5B). 6.…”