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The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28.

  • Author(s): Muller, Yannick D
  • Nguyen, Duy P
  • Ferreira, Leonardo MR
  • Ho, Patrick
  • Raffin, Caroline
  • Valencia, Roxxana Valeria Beltran
  • Congrave-Wilson, Zion
  • Roth, Theodore L
  • Eyquem, Justin
  • Van Gool, Frederic
  • Marson, Alexander
  • Perez, Laurent
  • Wells, James A
  • Bluestone, Jeffrey A
  • Tang, Qizhi
  • et al.
Abstract

Anti-CD19 chimeric antigen receptor (CD19-CAR)-engineered T cells are approved therapeutics for malignancies. The impact of the hinge domain (HD) and the transmembrane domain (TMD) between the extracellular antigen-targeting CARs and the intracellular signaling modalities of CARs has not been systemically studied. In this study, a series of 19-CARs differing only by their HD (CD8, CD28, or IgG4) and TMD (CD8 or CD28) was generated. CARs containing a CD28-TMD, but not a CD8-TMD, formed heterodimers with the endogenous CD28 in human T cells, as shown by co-immunoprecipitation and CAR-dependent proliferation of anti-CD28 stimulation. This dimerization was dependent on polar amino acids in the CD28-TMD and was more efficient with CARs containing CD28 or CD8 HD than IgG4-HD. The CD28-CAR heterodimers did not respond to CD80 and CD86 stimulation but had a significantly reduced CD28 cell-surface expression. These data unveiled a fundamental difference between CD28-TMD and CD8-TMD and indicated that CD28-TMD can modulate CAR T-cell activities by engaging endogenous partners.

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