Design of TCR Structural Variants That Retain or Invert the Normal Activation Signal.
Immunohorizons
; 5(5): 349-359, 2021 05 26.
Article
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| MEDLINE
| ID: mdl-34039676
ABSTRACT
We designed variant human TCRs composed of the full-length TCRα/ß or extracellular and transmembrane domains of the associated CD3 subunits fused to polypeptides derived from proteins thought to either enhance or inhibit normal T cell function. First, we showed that the C termini of both the TCR α- and ß-chains can accommodate specific additional sequences, without abrogating complex formation or acute sensitivity of the receptor. Replacement of ITAMs with ITIM-containing intracellular domains inverted the TCR signal (i.e., created a ligand-dependent inhibitory receptor). The normal signaling function of the CD3 complex was transferable to the TCR by eliminating all CD3 ITAMs and grafting three to six ITAMs onto the C termini of the α/ß-chains, with no effect on acute sensitivity. The observation that TCR variants of such diverse C-terminal composition can fold and function as signaling receptors demonstrates substantial structural and functional malleability of TCRs. These results add to knowledge about TCR structure-function with regard to acute signaling and may provide a route to use TCRs in different ways for T cell therapy.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Receptores de Antígenos de Linfocitos T
/
Linfocitos T
/
Transducción de Señal
/
Complejo Receptor-CD3 del Antígeno de Linfocito T
Límite:
Humans
Idioma:
En
Revista:
Immunohorizons
Año:
2021
Tipo del documento:
Article