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Identification of a murine CD28 dileucine motif that suppresses single-chain chimeric T-cell receptor expression and function.
- Source :
-
Blood [Blood] 2003 Dec 15; Vol. 102 (13), pp. 4320-5. Date of Electronic Publication: 2003 Aug 28. - Publication Year :
- 2003
-
Abstract
- Recent preclinical and clinical trials have demonstrated the therapeutic potential of T lymphocytes redirected with genetically engineered T-cell receptor (TCR) surrogates against infected, cancerous, or autoreactive cells. These surrogate TCRs link a ligand-recognition domain to signaling regions from the TCR. We previously compared the function of surrogate TCRs that include TCR or TCR and CD28 signaling regions. We found that primary murine T cells modified to specifically target Kb-restricted CD8+ T cells using either Kb-zeta or Kb-CD28-zeta receptors had similar functional activities, although the CD28-zeta receptor showed a 2-fold to 4-fold decreased expression. We have now identified a previously unrecognized dileucine motif in the murine CD28 signaling domain that accounts for this reduced expression. Inactivation of this motif increased chimeric receptor surface expression 2- to 5-fold. T cells expressing the dileucine-mutated CD28-zeta chimeric receptor demonstrated enhanced proliferation, cytokine production, and cytolytic activities. Further, cells expressing this dileucine-mutated receptor were highly effective in eliminating antigen-specific CD8+ T lymphocytes in vivo. These results therefore identify a critical motif limiting the function of receptor-modified T lymphocytes, demonstrate that inactivation of this motif enhances chimeric receptor function, and illustrate a potential novel application of receptor-modified T lymphocytes in the induction of immune tolerance.
- Subjects :
- Amino Acid Motifs
Animals
CD28 Antigens biosynthesis
CD28 Antigens genetics
Cytotoxicity, Immunologic
Gene Expression Regulation
H-2 Antigens chemistry
H-2 Antigens genetics
Immune Tolerance
Interferon-gamma metabolism
Leucine chemistry
Membrane Proteins biosynthesis
Mice
Mice, Transgenic
Receptors, Antigen, T-Cell biosynthesis
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins immunology
CD28 Antigens chemistry
Membrane Proteins genetics
Receptors, Antigen, T-Cell genetics
T-Lymphocytes, Cytotoxic immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 102
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 12946999
- Full Text :
- https://doi.org/10.1182/blood-2003-04-1255