Identification of a murine CD28 dileucine motif that suppresses single-chain chimeric T-cell receptor expression and function

2003/09/02 by Phuong Nguyen, Ioana Moisini, Terrence L. Geiger · 15 citations
Medicine · Immunology and Microbiology · #CAR-T cell therapy research #T-cell and B-cell Immunology #Immune Cell Function and Interaction

paper · doi:10.1182/blood-2003-04-1255

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.

Citations

• Integrated src kinase and costimulatory activity enhances signal transduction through single-chain chimeric receptors in T lymphocytes

Cited by

• Modulating AP-1 enables CAR T cells to establish an intratumoral stemlike reservoir and overcomes resistance to PD-1 blockade
• 4-1BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies. [europepmc]
• An NKp30-based chimeric antigen receptor promotes T cell effector functions and antitumor efficacy in vivo. [europepmc]
• Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. [europepmc]
• Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. [europepmc]
• Rewiring T-cell responses to soluble factors with chimeric antigen receptors. [europepmc]
• TGF-β-responsive CAR-T cells promote anti-tumor immune function. [europepmc]
• Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function. [europepmc]
• Strategies to Address Chimeric Antigen Receptor Tonic Signaling. [europepmc]
• Manufacturing and preclinical validation of CAR T cells targeting ICAM-1 for advanced thyroid cancer therapy. [europepmc]
• Development and characterisation of NKp44-based chimeric antigen receptors that confer T cells with NK cell-like specificity. [europepmc]
• Specific Activation of T Cells by an ACE2-Based CAR-Like Receptor upon Recognition of SARS-CoV-2 Spike Protein. [europepmc]
• The Combination of Oncolytic Virus and Antibody Blockade of TGF-β Enhances the Efficacy of αvβ6-Targeting CAR T Cells Against Pancreatic Cancer in an Immunocompetent Model. [europepmc]
• Chimeric antigen receptors discriminate between tau and distinct amyloid-beta species. [europepmc]
• A CD8αβ co-receptor modified to contain an intracellular CD28 signaling tail enhances TCR-engineered T cell function independent of solid-tumor-associated co-stimulatory ligands. [europepmc]

Related

• Antigen‐specific targeting of CD28‐mediated T cell co‐stimulation using chimeric single‐chain antibody variable fragment‐CD28 receptors
• Integrated src kinase and costimulatory activity enhances signal transduction through single-chain chimeric receptors in T lymphocytes
• TCR modifications that enhance chain pairing in gene-modified T cells can augment cross-reactivity and alleviate CD8 dependence
• Cytotoxic CD8+ T cells in cancer and cancer immunotherapy
• Targeting of acute myeloid leukemia by five-gene engineered T cells expressing transgenic T-cell receptor specific to WT1, chimeric antigenic receptor specific to GM-CSF receptor, bispecific T-cell engager specific to CD33, and tEGFR suicide gene system