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

Nadine Pouw, Elike Treffers-Westerlaken, Anna Mondino, Cor Lamers, Reno Debets

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 TCRαβ transgenes and enhanced fractions of CD62Lhi, CD44lo 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 IFNγ 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.

Original languageEnglish
Pages (from-to)1411-1420
Number of pages10
JournalMolecular Immunology
Volume47
Issue number7-8
DOIs
Publication statusPublished - Apr 2010

Fingerprint

Interleukin-15
Differentiation Antigens
T-Lymphocytes
Genes
Concanavalin A
Genetic Therapy
interleukin-21
Cell Differentiation
T Lymphocyte Differentiation Antigens
T-Cell Antigen Receptor Specificity
Cytokines
Polystyrenes
Cell- and Tissue-Based Therapy
Transgenes
Lectins
Interleukin-2
Melanoma
Therapeutics

Keywords

  • Common-γ cytokines
  • Primary T lymphocytes
  • Retroviral transduction
  • T cell activation
  • T cell differentiation
  • TCR transgenes

ASJC Scopus subject areas

  • Molecular Biology
  • Immunology

Cite this

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. / Pouw, Nadine; Treffers-Westerlaken, Elike; Mondino, Anna; Lamers, Cor; Debets, Reno.

In: Molecular Immunology, Vol. 47, No. 7-8, 04.2010, p. 1411-1420.

Research output: Contribution to journalArticle

@article{8e6f5736aa2f4d5f86ebdfc69c971c7c,
title = "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",
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 TCRαβ transgenes and enhanced fractions of CD62Lhi, CD44lo 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 IFNγ 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.",
keywords = "Common-γ cytokines, Primary T lymphocytes, Retroviral transduction, T cell activation, T cell differentiation, TCR transgenes",
author = "Nadine Pouw and Elike Treffers-Westerlaken and Anna Mondino and Cor Lamers and Reno Debets",
year = "2010",
month = "4",
doi = "10.1016/j.molimm.2010.02.022",
language = "English",
volume = "47",
pages = "1411--1420",
journal = "Molecular Immunology",
issn = "0161-5890",
publisher = "Elsevier Limited",
number = "7-8",

}

TY - JOUR

T1 - TCR gene-engineered T cell

T2 - Limited T cell activation and combined use of IL-15 and IL-21 ensure minimal differentiation and maximal antigen-specificity

AU - Pouw, Nadine

AU - Treffers-Westerlaken, Elike

AU - Mondino, Anna

AU - Lamers, Cor

AU - Debets, Reno

PY - 2010/4

Y1 - 2010/4

N2 - 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 TCRαβ transgenes and enhanced fractions of CD62Lhi, CD44lo 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 IFNγ 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.

AB - 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 TCRαβ transgenes and enhanced fractions of CD62Lhi, CD44lo 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 IFNγ 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.

KW - Common-γ cytokines

KW - Primary T lymphocytes

KW - Retroviral transduction

KW - T cell activation

KW - T cell differentiation

KW - TCR transgenes

UR - http://www.scopus.com/inward/record.url?scp=77950603634&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950603634&partnerID=8YFLogxK

U2 - 10.1016/j.molimm.2010.02.022

DO - 10.1016/j.molimm.2010.02.022

M3 - Article

VL - 47

SP - 1411

EP - 1420

JO - Molecular Immunology

JF - Molecular Immunology

SN - 0161-5890

IS - 7-8

ER -