Antigen-dependent CD28 Signaling Selectively Enhances Survival and Proliferation in Genetically Modified Activated Human Primary T Lymphocytes

Krause, Anja; Guo, Hong-Fen; Latouche, Jean-Baptiste; Tan, Cen; Cheung, Nai‐Kong V.; Sadelain, Michel

doi:10.1084/jem.188.4.619

Cited by 270 publications

(199 citation statements)

References 45 publications

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“…Similar to chimeric receptors containing the TCR-and Fc⑀RI-␥ signaling chains, engagement of a chimera containing the intracellular domain of CD28 has also been shown to transduce costimulatory signals equivalent to those mediated upon ligation of endogenous CD28 receptors (42,43). Although the ability of CD28 to transduce signals distinct from the TCR remains unresolved, CD28 may influence immediate and sustained TCR signaling by the recruitment of phosphatidylinositol-3-kinase and tyrosine kinase Itk and activation of Src family kinases such as Lck, mediated by different motifs within the cytoplasmic tail (44 -47).…”

Section: Discussionmentioning

confidence: 99%

Rejection of Syngeneic Colon Carcinoma by CTLs Expressing Single-Chain Antibody Receptors Codelivering CD28 Costimulation

Haynes

Trapani

Teng

et al. 2002

The Journal of Immunology

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A new strategy to improve the therapeutic utility of redirected T cells for cancer involves the development of novel Ag-specific chimeric receptors capable of stimulating optimal and sustained T cell antitumor activity in vivo. Given that T cells require both primary and costimulatory signals for optimal activation and that many tumors do not express critical costimulatory ligands, modified single-chain Ab receptors have been engineered to codeliver CD28 costimulation. In this study, we have compared the antitumor potency of primary T lymphocytes expressing carcinoembryonic Ag (CEA)-reactive chimeric receptors that incorporate either TCR-ζ or CD28/TCR-ζ signaling. Although both receptor-transduced T cell effector populations demonstrated cytolysis of CEA+ tumors in vitro, T cells expressing the single-chain variable fragment of Ig (scFv)-CD28-ζ chimera had a far greater capacity to control the growth of CEA+ xenogeneic and syngeneic colon carcinomas in vivo. The observed enhanced antitumor activity of T cells expressing the scFv-CD28-ζ receptor was critically dependent on perforin and the production of IFN-γ. Overall, this study has illustrated the ability of a chimeric scFv receptor capable of harnessing the signaling machinery of both TCR-ζ and CD28 to augment T cell immunity against tumors that have lost expression of both MHC/peptide and costimulatory ligands in vivo.

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Section: Discussionmentioning

confidence: 99%

Rejection of Syngeneic Colon Carcinoma by CTLs Expressing Single-Chain Antibody Receptors Codelivering CD28 Costimulation

Haynes

Trapani

Teng

et al. 2002

The Journal of Immunology

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“…Washed transduced T cells were stimulated in 96-well flat-bottom plates (1 ϫ 10 5 cells/well in a 200 l total volume) with combinations of OKT3 or OKT8 mAb (both plate-bound by preincubation of plates with 1 g/ml Ab), soluble CD28.2 mAb (1 g/ml), soluble 9.6 mAb (CD2, 1 g/ml; a gift from Dr. J. Ledbetter, Bristol-Myers Squibb) and PMA (varying concentrations as indicated) plus ionomycin (1 M) as described (38). After 24 h, supernatants were harvested and assayed for IL-2 content with the use of IL-2 ELISA kits (R&D Systems, Minneapolis, MN).…”

Section: Il-2 Inductionmentioning

confidence: 99%

Negative-Feedback Regulation of CD28 Costimulation by a Novel Mitogen-Activated Protein Kinase Phosphatase, MKP6

Martí

Krause

Post

et al. 2001

The Journal of Immunology

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TCR and CD28 costimulatory receptor-cooperative induction of T cell IL-2 secretion is dependent upon activation of mitogen-activated protein (MAP) kinases. Using yeast-hybrid technology, we cloned a novel CD28 cytoplasmic tail (CD28 CYT) interacting protein, MAP kinase phosphatase-6 (MKP6), which we demonstrate inactivates MAP kinases. Several lines of evidence indicate that MKP6 plays an important functional role in CD28 costimulatory signaling. First, in human peripheral blood T cells (PBT), expression of MKP6 is strongly up-regulated by CD28 costimulation. Second, transfer of dominant-negative MKP6 to PBT with the use of retroviruses primes PBT for the secretion of substantially larger quantities of IL-2, specifically in response to CD28 costimulation. A similar enhancement of IL-2 secretion is observed neither in response to TCR plus CD2 costimulatory receptor engagement nor in response to other mitogenic stimuli such as phorbol ester and ionomycin. Furthermore, this hypersensitivity to CD28 costimulation is associated with CD28-mediated hyperactivation of MAP kinases. Third, a retroviral transduced chimeric receptor with a CD28 CYT that is specifically unable to bind MKP6 costimulates considerably larger quantities of IL-2 from PBT than a similar transduced chimeric receptor that contains a wild-type CD28 CYT. Taken together, these results suggest that MKP6 functions as a novel negative-feedback regulator of CD28 costimulatory signaling that controls the activation of MAP kinases.

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“…The addition of the CD28 signaling tail to TCR-z in the signaling domain has been shown to enhance RMTC survival and function in several studies. [19][20][21] We also inserted a L-G mutation at the N terminus of the CD28 sequence because studies of the K b -CD28-z construct showed this to enhance expression by disrupting a potentially cryptic dileucine motif. 22 Receptor cDNA was subcloned into a murine stem cell virus (MSCV)-driven retroviral expression vector that included an internal ribosome entry site-linked GFP (MSCV-I-GFP), and recombinant retrovirus was used to transduce stimulated primary T lymphocytes.…”

Section: Resultsmentioning

confidence: 99%

Induction of tolerance and immunity by redirected B cell-specific cytolytic T lymphocytes

2007

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Chimeric receptors bearing ligand recognition domains linked to signaling regions from the T-cell receptor can redirect T lymphocytes against non-MHC-restricted targets. Cytolytic T lymphocytes (CTL) expressing these chimeric receptors are being tested in preclinical and clinical trials for activity in cancer, infectious diseases and autoimmunity. The chimeric receptors may incorporate antigenic epitopes previously unrecognized by the immune system. Whether a receptorspecific antibody response develops to these neoantigens and whether such a response inhibits therapeutic cell activity is unknown. We hypothesized that upon engagement of a chimeric receptor-specific B cell, receptor-modified CTL will be activated, lysing the B cell and inducing tolerance to the chimeric receptor rather than immunity. We demonstrate that receptor-modified CTL are indeed stimulated by cognate receptor-specific B cells, proliferate and produce cytokines in response and kill the B cells in vitro and in vivo. However, this is insufficient to induce full B-cell tolerance. Modified CTL induce a chimeric receptor-specific antibody response independent of any other source of antigen. Nevertheless, the CTL retain substantial activity even in the presence of saturating doses of receptor-specific antibody. Thus antichimeric receptor antibody responses need to be considered in the clinical use of chimeric receptor-modified T cells. However, the inhibitory activity of these antibodies may in cases be limited.

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Antigen-dependent CD28 Signaling Selectively Enhances Survival and Proliferation in Genetically Modified Activated Human Primary T Lymphocytes

Cited by 270 publications

References 45 publications

Rejection of Syngeneic Colon Carcinoma by CTLs Expressing Single-Chain Antibody Receptors Codelivering CD28 Costimulation

Rejection of Syngeneic Colon Carcinoma by CTLs Expressing Single-Chain Antibody Receptors Codelivering CD28 Costimulation

Negative-Feedback Regulation of CD28 Costimulation by a Novel Mitogen-Activated Protein Kinase Phosphatase, MKP6

Induction of tolerance and immunity by redirected B cell-specific cytolytic T lymphocytes

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