2B4 (CD244) signaling via chimeric receptors costimulates tumor-antigen specific proliferation and in vitro expansion of human T cells.
Regulatory NK cell receptors can contribute to antigen-specific adaptive immune responses by modulating T cell receptor (TCR)-induced T cell activation. We investigated the potential of the NK cell receptor 2B4 (CD244) to enhance tumor antigen-induced activation of human T cells. 2B4 is a member of the CD2 receptor subfamily with both activating and inhibitory functions in NK cells. In T cells, its expression is positively associated with the acquisition of a cytolytic effector memory phenotype. Recombinant chimeric receptors that link extracellular single-chain Fv fragments specific for the tumor-associated surface antigens CD19 and G(D2) to the signaling domains of human 2B4 and/or TCRzeta were expressed in non-specifically activated peripheral blood T cells by retroviral gene transfer. While 2B4 signaling alone failed to induce T cell effector functions or proliferation, it significantly augmented the antigen-specific activation responses induced by TCRzeta. 2B4 costimulation did not affect the predominant effector memory phenotype of expanding T cells, nor did it increase the proportion of T cells with regulatory phenotype (CD4+CD25(hi)FoxP3+). These data support a costimulatory role for 2B4 in human T cell subpopulations. As an amplifier of TCR-mediated signals, 2B4 may provide a powerful new tool for immunotherapy of cancer, promoting sustained activation and proliferation of gene-modified antitumor T cells.
Altvater
Bianca
B
Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Münster, Germany.
Landmeier
Silke
S
Pscherer
Sibylle
S
Temme
Jaane
J
Juergens
Heribert
H
Pule
Martin
M
Rossig
Claudia
C
D017951:Antigen Presentation; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D048708:Cell Growth Processes / Q000276:immunology; D045744:Cell Line, Tumor; D000939:Epitopes; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D000071176:Signaling Lymphocytic Activation Molecule Family; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; C084093:CD244 protein, human; D000939:Epitopes; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D000071176:Signaling Lymphocytic Activation Molecule Family; D007371:Interferon-gamma