Distinct role of lymphocyte function-associated antigen-1 in mediating effective cytolytic activity by cytotoxic T lymphocytes

Abstract

Lymphocyte function-associated antigen-1 (LFA-1) interaction with intercellular adhesion molecules (ICAMs) facilitates T cell antigen receptor (TCR)-mediated killing. To dissect TCR and LFA-1 contributions, we evaluated cytolytic activity and granule release by cytotoxic T lymphocytes (CTL) as well as intracellular granule redistribution and morphology of CTL stimulated with natural TCR ligand in the presence or absence of LFA-1 engagement. Although other adhesion mechanisms, e.g., CD2-CD58 interaction, could substitute for LFA-1 to trigger CTL degranulation, productive LFA-1 ligation was indispensable for effective target cell lysis by the released granules. LFA-1-mediated adhesion to glass-supported bilayers containing intercellular adhesion molecule-1 was characterized by a much larger junction area, marked by LFA-1 segregation, and a more compact cell shape compared with those observed for CD2-mediated adhesion to bilayers containing CD58. A larger contact induced by intercellular adhesion molecule 1 determined a unique positioning of granules near the interface. These data provide evidence that LFA-1 delivers a distinct signal essential for directing released cytolytic granules to the surface of antigenbearing target cells to mediate the effective destruction of these cells by CTL.cytolytic granules ͉ immunological synapse ͉ T cell receptor K illing of virus-infected cells by cytotoxic T lymphocytes (CTL) is triggered by interactions of T cell antigen receptor (TCR) with viral peptides presented by MHC class I proteins on the surface of infected cells and can be mediated by cytotoxic granule exocytosis or FasL-Fas interaction (1, 2). This is a sensitive response often requiring less than a dozen cognate peptide-MHC [complex of antigenic peptide with MHC protein (pMHC)] complexes on the target cell (3, 4). Although productive TCR engagement is necessary and essential to induce CTL cytolytic activity, other accessory and costimulatory molecules are thought to play a role in mediating CTL degranulation and effective cytolytic activity of released granules. For example, both lymphocyte function-associated antigen-1 (LFA-1) and CD2 contribute to CTL adhesion and killing of target cells (5). Ligation of LFA-1 on CTL by high densities of intercellular adhesion molecule-1 (ICAM-1) is sufficient to initiate large-scale molecular segregation and formation of peripheral supramolecular-activating cluster (6), which typically requires antigen for helper T cells (7,8) and CTL precursors (9). In contrast, ligation of CD2 with its natural ligand CD58 (5) mediates formation of a very small adhesion area by CTL (10). However, how specifically LFA-1, CD2, and other adhesion molecules mediate granuleinduced cytotoxicity has not been defined.Here we have investigated the role of productive LFA-1 engagement for antigen-induced granule release and target cell lysis in vitro as well as for granule polarization in CTL exposed to the glasssupported bilayer. We have found that, although blocking of LFA-1-ICAM-1 interaction abrogates ...

Cytotoxic immunological synapses do not restrict the action of interferon-γ to antigenic target cells

“…3F is due to the LFA-1-dependent properties of the immunological synapse. This loss of restriction is reminiscent of the diminution of CTL cytotoxicity with impaired focusing of CTL lytic granules onto target cells following disruption of the peripheral SMAC by LFA-1 blocking antibodies (14).…”

CD8+CD103+ Tumor–Infiltrating Lymphocytes Are Tumor-Specific Tissue-Resident Memory T Cells and a Prognostic Factor for Survival in Lung Cancer Patients

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Epigallocatechin-3-gallate (EGCG) Suppresses the Trafficking of Lymphocytes to Epidermal Melanocytes <i>via</i> Inhibition of JAK2: Its Implication for Vitiligo Treatment

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