Part:BBa_K4175003

human intracellular PD-1

This part is the intracellular domain of human programmed death-1 (PD-1) (aa 191-289).

Sequence and Features

Assembly Compatibility:

• 10
  COMPATIBLE WITH RFC[10]
• 12
  COMPATIBLE WITH RFC[12]
• 21
  COMPATIBLE WITH RFC[21]
• 23
  COMPATIBLE WITH RFC[23]
• 25
  COMPATIBLE WITH RFC[25]
• 1000
  COMPATIBLE WITH RFC[1000]

Biology

PD-1 acts as an inhibitory ‘checkpoint’ upon T cell activation to prevent T cells from attacking healthy cells (Sharpe and Pauken, 2018). In the early phase of T cell activation, PD-1 is expressed on the membrane of effector T cells. When programmed death-ligand 1 (PD-L1) and PD-L2 on the antigen-presenting cells (APCs) bind to PD-1, the immunoreceptor tyrosine-based switch motif (ITSM) in the intracellular part of PD-1 will recruit phosphatases such as SHP2 (Fig 1). These phosphatases can then disturb the positive signal exerted by T cell receptors (TCR) by inhibiting ZAP70, and PI3K-AKT and RAS signaling pathway. Notably, the TCR signaling can only be inhibited by PD-1 when PD-L1 or PD-L2 is presented on the same cell where the antigen for TCR recognition is presented (Sharpe and Pauken, 2018). As a result, the activation of various transcriptional factors, such as AP-1, NFAT and NF-κB is decreased, leading to decreased T cell activation, proliferation and survival. It has also been found that PD-1 can trigger basic leucine zipper transcriptional factor ATF-like (BATF) activation, which has negative effect on TCR signaling (Sharpe and Pauken, 2018).

Usage

PD-1 acts as an inhibitory ‘checkpoint’ upon T cell activation to prevent T cells from attacking healthy cells (Sharpe and Pauken, 2018). In the early phase of T cell activation, PD-1 is expressed on the membrane of effector T cells. When programmed death-ligand 1 (PD-L1) and PD-L2 on the antigen-presenting cells (APCs) bind to PD-1, the immunoreceptor tyrosine-based switch motif (ITSM) in the intracellular part of PD-1 will recruit phosphatases such as SHP2 (Fig 1). These phosphatases can then disturb the positive signal exerted by T cell receptors (TCR) by inhibiting ZAP70, and PI3K-AKT and RAS signaling pathway. Notably, the TCR signaling can only be inhibited by PD-1 when PD-L1 or PD-L2 is presented on the same cell where the antigen for TCR recognition is presented (Sharpe and Pauken, 2018). As a result, the activation of various transcriptional factors, such as AP-1, NFAT and NF-κB is decreased, leading to decreased T cell activation, proliferation and survival. It has also been found that PD-1 can trigger basic leucine zipper transcriptional factor ATF-like (BATF) activation, which has negative effect on TCR signaling (Sharpe and Pauken, 2018).

Reference

Fedorov, V.D., Themeli, M., Sadelain, M., 2013. PD-1– and CTLA-4–Based Inhibitory Chimeric Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses. Sci. Transl. Med. 5, 215ra172. https://doi.org/10.1126/scitranslmed.3006597

Sharpe, A.H., Pauken, K.E., 2018. The diverse functions of the PD1 inhibitory pathway. Nat. Rev. Immunol. 18, 153–167. https://doi.org/10.1038/nri.2017.108