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      TCR gene-engineered T cell: Limited T cell activation and combined use of IL-15 and IL-21 ensure minimal differentiation and maximal antigen-specificity

      , , , ,
      Molecular Immunology
      Elsevier BV

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          Abstract

          Clinical TCR gene therapy of melanoma represents a feasible and promising treatment rationale yet is currently challenged by objective response rates that stay behind those observed with conventional adoptive T cell therapy. Here, the phenotype and function of TCR-transduced T cells, considered to determine the efficacy of TCR gene therapy, were studied in relation to T cell activation and cytokine treatments. We observed that the lectin Concanavalin A (ConA), and to a lesser extent anti-CD3 and CD28 mAbs (soluble CD3/CD28), resulted in functional surface expression of the TCRalphabeta transgenes and enhanced fractions of CD62L(hi), CD44(lo) naive T cells. T cell functions and limited T cell differentiation were most significant when T cells were treated with a combination of IL-15 and IL-21 rather than IL-2. In comparison, anti-CD3 and CD28 mAbs coated to either latex or polystyrene beads (polystyrene or latex CD3/CD28) resulted in improved TCR expression levels and enhanced T cell differentiation irrespective of cytokine treatment, with effects most pronounced for polystyrene CD3/CD28. T cells demonstrated enhanced cytotoxic activity and IFNgamma production when activated with CD3/CD28 beads and treated with IL-15 and IL-21, but at the same time displayed non-specific T cell responses. In contrast, ConA and soluble CD3/CD28 activations resulted in antigen-specific T cell responses. In short, we show that retroviral TCR engineering of primary T cells benefits from activation with ConA or soluble CD3/CD28 rather than immobilized anti-CD3 and CD28 mAbs with respect to T cell differentiation and antigen-specificity of T cell responses. Copyright 2010 Elsevier Ltd. All rights reserved.

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          Author and article information

          Journal
          Molecular Immunology
          Molecular Immunology
          Elsevier BV
          01615890
          April 2010
          April 2010
          : 47
          : 7-8
          : 1411-1420
          Article
          10.1016/j.molimm.2010.02.022
          20303179
          9167513d-2101-4e91-9d41-a21c7aaeaa68
          © 2010

          https://www.elsevier.com/tdm/userlicense/1.0/

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