Ligation of the CD2 co-stimulatory receptor enhances IL-2 production from first-generation chimeric antigen receptor T cells

Gene Ther. 2012 Nov;19(11):1114-20. doi: 10.1038/gt.2011.192. Epub 2011 Dec 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • CD2 Antigens / immunology
  • CD2 Antigens / metabolism*
  • CD28 Antigens / immunology
  • CD28 Antigens / metabolism
  • CD48 Antigen
  • CD58 Antigens / immunology
  • CD58 Antigens / metabolism
  • Cell Line
  • Humans
  • Interleukin-2 / biosynthesis*
  • Ligands
  • Mice
  • Protein Binding
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*

Substances

  • Antigens, CD
  • CD2 Antigens
  • CD28 Antigens
  • CD48 Antigen
  • CD48 protein, human
  • CD58 Antigens
  • Cd48 protein, mouse
  • Interleukin-2
  • Ligands
  • Receptors, Antigen, T-Cell