title: Ligation of the CD2 co-stimulatory receptor enhances IL-2 production from first-generation chimeric antigen receptor T cells.
abstract: T cells bearing chimeric antigen receptors (CARs) are broadly categorised into first- and second-generation receptors. Second-generation CARs contain a co-stimulatory signalling molecule and have been shown to secrete IL-2, undergo greater proliferation and to have enhanced persistence in vivo. However, we have shown that T cells bearing a first-generation CAR containing a CD19-targeting scFv (single-chain variable fragment) and the CD3ζ-signalling domain are able to produce IL-2 upon co-culture with CD19(+) B-cell lymphomas independent of CD28 activity. Here, we report that signalling through endogenous CD2 following ligation with its ligands, CD48 in mouse and CD58 in humans, drives IL-2 production by first-generation CD19-specific CAR. Moreover, the high levels of IL-2 produced by human T cells engrafted with a second-generation CD28-containing CAR during target-cell recognition are dependent to a degree upon CD2 receptor activity. These observations highlight the fact that the functional activity induced by T-cell-expressed CARs is dependent upon endogenous 'natural' receptor interactions. A deeper understanding of the role of these activities will serve to further refine the design of future CARs to either exploit or avoid these interactions.
authors: Clinical and Experimental Immunotherapy Group, Department of Medical Oncology, School of Cancer and Enabling Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors: E J
authors: EJ
authors: Cheadle
authors: D G
authors: DG
authors: Rothwell
authors: J S
authors: JS
authors: Bridgeman
authors: V E
authors: VE
authors: Sheard
authors: R E
authors: RE
authors: Hawkins
authors: D E
authors: DE
authors: Gilham
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D018801:CD2 Antigens / Q000276:immunology / Q000378:metabolism*; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D000071178:CD48 Antigen; D018968:CD58 Antigens / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D008024:Ligands; D051379:Mice; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D018801:CD2 Antigens; D018106:CD28 Antigens; D000071178:CD48 Antigen; C000604065:CD48 protein, human; D018968:CD58 Antigens; C000604066:Cd48 protein, mouse; D007376:Interleukin-2; D008024:Ligands; D011948:Receptors, Antigen, T-Cell