Difference between revisions of "Part:BBa K5310010:Design"

Latest revision as of 09:46, 30 September 2024

CD137 signalling domain

Design Notes

The sequence was retrieved from the NCBI database, the domain's use was evaluated in the literature, and the sequence was codon optimized for expression in human primary cell lines.

It has been demonstrated in literature that the main activation domain benefits from the existence of co-stimulatory sequences that amplify signaling and prolong CAR T-cell survival. While this started with a single co-stimulatory endodomain (2nd generation), it was quickly established that a combination (3rd generation) produces better results. The domains used almost exclusively are CD28 (encoded by BBa_K5310009) and 4-1BB (encoded by BBa_K5310010).

4-1BB belongs to the TNF receptor family and promotes T-cell proliferation via a pathway called ncNF-κB (non-canonical nuclear factor κB). Upon ligand-induced trimerization of 4-1BB, TNF receptor–associated factors (TRAF) are recruited, shifting ubiquitination from NIK to TRAF3. NIK, which is normally ubiquitinated and degraded, can now accumulate and trigger a signaling cascade that ends with the activation of important lymphocyte development genes.

Source

The 4-1-BB signalling domain sequence was retrieved from the CD28 gene that resides on chromosome 2 of the human genome.

References

1. Tomasik, J., Jasiński, M., & Basak, G. W. (2022). Next generations of CAR-T cells - new therapeutic opportunities in hematology? In Frontiers in Immunology (Vol. 13). Frontiers Media S.A. https://doi.org/10.3389/fimmu.2022.1034707

2. Philipson, B. I., O’Connor, R. S., May, M. J., June, C. H., Albelda, S. M., & Milone, M. C. (2020). 4-1BB costimulation promotes CAR T cell survival through noncanonical NF-κB signaling. Science Signaling, 13(625). https://doi.org/10.1126/scisignal.aay8248