Impact of chimeric immune receptor extracellular protein domains on T cell function

Abstract

Chimeric immune receptors (CIR) encompass tumor-or were constructed to include alternative extracellular spacer virus-specific ligands or antibodies fused to the signaling and transmembrane protein domains derived from memdomains of either the T cell receptor or Fc receptor. T cells bers of the immunoglobulin supergene family. The effect of expressing these receptors recapitulate the cytopathic these alternative extracellular protein domains on receptor effects mediated by the T cell receptor and allow the tarstability, antigen affinity and T cell activity was assessed. geting of tumor or virus infected cells in an MHC-indeWe demonstrate that modifying the extracellular protein pendent manner. With this technology, large numbers of T domains of the anti-HIV env CIRs significantly impacted cells with redirected target specificity can be generated. To receptor stability and substrate binding affinity and that define the structural features of recombinant CIRs required these effects, and not simply the level of cell surface for optimal function, a panel of five closely related CIRs expression, correlated most strongly with changes in CIRwith identical target specificity were generated. These mediated killing. These studies will aid in the rationale receptors recognized HIV env through the single chain Fv design of recombinant CIRs for the immunotherapy of viral (scFv) of an anti-gp120 antibody. These scFv-receptors infections, cancer and other diseases.

Antitumor activity of dual-specific T cells and influenza virus

“…For example, changes to the hinge region may result in improved function as has been demonstrated previously for some chimeric receptors. [30][31][32] It is not clear what proportion of the bulk T cell population were dual specific at a single cell level, although all T cells had integrated the retroviral gene encoding the chimeric receptor and neomycin phosphotransferase, since the neomycin analog G418 was used in the cell culture period. Some insight into the likely Antitumor dual-specific T cells A Murphy et al proportion of dual-specific T cells can be gained from previous studies that characterized human dual-specific T cells, which are readily cloned (in contrast to mouse T cells), where 30-40% of T cells in the bulk population were demonstrated to be reactive with two antigens following transduction with a chimeric receptor.…”

T cell activation by recombinant FcεRI γ-chain immune receptors: an extracellular spacer domain impairs antigen-dependent T cell activation but not antigen recognition

“…6 Like ␥ chain receptors, the spacer domain affects the affinity of chain receptors for ligand and impairs receptor-mediated cytolysis. 8 Therefore, the high impact of an extracellular constant domain on the signaling function of recombinant receptors calls for a more rational design of the receptor molecule based on the modular components, particularly the signaling domain. Due to stable expression without the necessity of a spacer domain, we suggest that the basic scFv-␥ chain receptor configuration is preferred in the application of the chimeric receptor strategy in order to avoid that the extracellular spacer domain itself impairs receptor-mediated signaling and cellular activation.…”

“…7 Due to the lack of a rationale design and systematic determination of an optimal receptor configuration, it is still a matter of controversy whether modification of the basic receptor configuration by insertion of an heterologous protein spacer domain affects binding to ligand and/or transduction of the cell activation signal. Recently, Patel et al 8 reported that different extracellular spacer domains of a recombinant receptor harboring a CD3 signaling domain impair receptor-mediated target cell lysis. The stability of chain receptor expression itself, however, depends substantially on an appropriate spacer domain.…”

T-cell activation by recombinant immunoreceptors: Impact of the intracellular signalling domain on the stability of receptor expression and antigen-specific activation of grafted T cells

“…Previous studies indicate that dependent on the intracellular signalling domain and the type of grafted effector cell, the recombinant receptor may require an additional extracellular spacer domain for stable expression 11,12 that in turn also impacts its cell activation properties. 10,11 A rational design for the generation of highly efficient recombinant T-cell immunoreceptors must address both the receptor's cell surface expression and its cell activation properties that in turn modulate effector cell activation during prolonged propagation of receptor grafted T cells and the functional discrimination of membrane bound versus soluble target antigen required for efficient target cell elimination. On the other hand, our growing knowledge about the function of modularily composed immunoreceptors facilitates also the generation of receptors that exhibit restricted cellular activation properties thereby limiting the cellular response upon repeated restimulation.…”

“…[10][11][12] Recombinant z-chain receptors, in contrast to g-chain receptors, require an extracellular spacer domain for functional expression in T cells. 12 Although the requirements for functional expression of recombinant g-and z-chain receptors are obviously different, it remains unresolved how the transmembrane and/or intracellular signalling domain affects the stability of recombinant receptor expression on the cell surface and receptor-mediated cellular activation of grafted T cells.…”