Photophosphatidylserine Guides Natural Killer Cell Photoimmunotherapy via Tim-3

Abstract

Natural killer (NK) cells, in addition to their cytotoxicity function, harbor prominent cytokine production capabilities and contribute to regulating autoimmune responses. T-cell immunoglobulin and mucin domain containing protein-3 (Tim-3) is one of the inhibitory receptors on NK cells and a promising immune checkpoint target. We recently found that phosphatidylserine (PS) binding to Tim-3 can suppress NK cell activation. Therefore, based on the therapeutic potential of Tim-3 in NK-cell-mediated diseases, we developed a photoswitchable ligand of Tim-3, termed photophosphatidylserine (phoPS), that mimics the effects of PS. Upon 365 or 455 nm light irradiation, the isomer of phoPS cyclically conversed the cis/trans configuration, resulting in an active/inactive Tim-3 ligand, thus modulating the function of NK cells in vitro and in vivo. We also demonstrated that reversible phoPS enabled optical control of acute hepatitis. Together, phoPS may be an appealing tool for autoimmune diseases and cytokine storms in the future.

Photoinduced Concerted Dual Single-bond Rotation of a Nitrogen-containing System Realized by Chalcogen Substitution

“…Photoisomerization of multiple bonds, such as C=C and C=N double bonds, has been used in various fields. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] A photoinduced concerted bond rotation, where two or more adjacent bonds rotate simultaneously, is a rare phenomenon and is known to be essentially different from the well-studied photoinduced single chemical bond rotation because the reaction product, in which two or more bonds are isomerized from the starting material, can be directly afforded without the presence of intermediate isomers. 20,21 A simultaneous three-bond isomerization of a conjugated triene system 22 and Hula Twist (HT) of a hemithioindigo (HTI) motor 23,24 are only experimentally demonstrated photoinduced concerted rotations involving a C=C double bond.…”

Concise Synthesis of Glycerophospholipids

“…Recently, Yang et al reported the first synthesis of a photoswitchable diacyl phosphatidylserine, named phoPS following a chemoenzymatic route, and they evaluated the activity of this lipid in autoimmune diseases . Using the Co-catalyzed epoxide opening described here, we also report a four-step route to similar derivatives dAzoPS and oleoyl-AzoPS (Scheme ).…”

Importance of photophosphatidylserine and Tim-3 in photoimmunotherapy

“…They designed a photoswitchable ligand, which could efficiently be induced or inhibited at varying wavelengths of light to fully understand the involvement of Tim-3 in the immune responses and its potential as a pharmacological checkpoint blockade target in pathologies that are triggered by NK cells. 6…”

“…Yang et al synthesized an azobenzene moiety that is integrated within the tail end of PS which is a cis -olefin tail, further resulting in a photoswitchable tool called phoPS. 6 Precise spatiotemporal irradiation causes activation or inactivation of phoPS, facilitating optical regulation of NK cell initiation through Tim-3. After photomanipulation, analysis of binding kinetics revealed that cis -phoPS exhibits greater binding affinity to Tim-3 as compared to trans -phoPS.…”

“…They designed a photoswitchable ligand, which could efficiently be induced or inhibited at varying wavelengths of light to fully understand the involvement of Tim-3 in the immune responses and its potential as a pharmacological checkpoint blockade target in pathologies that are triggered by NK cells. 6 Photoswitchable molecules are useful for studying biochemical pathways because they have a wide range of uses, are relatively lesser toxic, have a higher spatiotemporal specificity, and are easily operable. Such research was done by Konrad et al, where the significance of azobenzene was explored.…”