Background/Purpose: Programmed Death-1 (PD-1) is an inhibitory co-receptor that is highly expressed in T lymphocytes.  The binding of PD-1 to its ligands, PD-L1 or PD-L2, is vital for the physiologic regulation of the immune system. Likewise, a major function of the PD-1 signaling pathway is the inhibition of self-reactive T cells, which serve to protect against autoimmune disease. PD-1 transmits its inhibitory effects by dephosphorylation of physically associated proximal signaling molecules that are downstream of the T cell receptor complex. At the cellular level, PD-1 activation can leads to depression of T-cell proliferation, impaired survival, and decreased interleukin-2 release.

Methods: Preliminary studies have shown that PD-1 also inhibits T cell adhesion, but little is known how this is mediated. In order to fill this gap, we investigated the role of PD-1 in T-cell adhesion by analyzing the major players in its TCR signaling pathway. We hypothesized that PD-1 inhibited adhesion by inhibiting Rap1, a small GTPase vital for effective T cell motility and adhesion.

Results: We identified that when PD-1 binds to its ligand PD-L2 there is an inhibition of Rap1 activation and LFA-1 mediated adhesion. We continued to show that C3G, a vital component of activating Rap1 and a more upstream element in the TCR signaling cascade, is dephosphorylated by PD-1.

Moreover, this was mediated by the phosphatases SHP-1 and SHP-2. Interestingly, we did not see these results downstream the inhibitory co-receptors, CTLA-4, proving that PD-1 works by a distinct mechanism.

Conclusion: We concluded that PD-1 inhibits Rap1 mediated adhesion by dephosphorylation of C3G utilizing the phosphatases SHP-1 and SHP-2. Further studies are underway to further characterize the regulation of these enzymes by PD-1.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/programmed-death-1-inhibits-t-cell-adhesion-by-regulating-rap1/