Journal Club 2025.05.23

^{Inhibitory immunoreceptors CD300a and CD300lf cooperate to regulate mast cell activation}

Gyemin noh

Hanbin Lee 1,2, Chigusa Nakahashi-Oda 1,3,�, Wenxin Lyu 1,2, Mamoru Tanaka1,4,
Akiyoshi Rai1,5, Yoichi Muramoto 1,5, Yaqiu Wang1,2, Seiya Mizuno6, Kazuko Shibuya 1,3, and
Akira Shibuya 1,3,7,�

Abstract
Mast cells (MCs) play a central role in allergic immune responses. MC activation is regulated by several inhibitory immunoreceptors. The CD300
family members CD300a and CD300lf recognize phospholipid ligands and inhibit the FcεRI-mediated activating signal in MCs. While CD300a
binds to phosphatidylserine (PS) to inhibit MCs activation, CD300lf function is less clear due to its ability to bind with ceramide and PS.
Moreover, it also remains blurring whether CD300a and CD300lf function independently, cooperatively, or by interfering with each other in regulating
MC activation. Using imaging and flow cytometric analyses of bone marrow-derived cultured MCs (BMMCs) from wild-type (WT),
Cd300a–/–, Cd300lf–/–, and Cd300a–/–Cd300lf–/– mice, we show that CD300lf and CD300a colocalized with PS externalized to the outer leaflet of
the plasma membrane with a polar formation upon activation, and CD300lf cooperates with CD300a to inhibit BMMCs activation. CD300lf also
colocalized with extracellular ceramide in addition to the internal PS on the cell surface, which results in stronger inhibition of MC activation than
CD300lf binding to PS alone. Similarly, although both Cd300a–/– and Cd300lf–/– mice showed decreased rectal temperatures compared with WT
mice in the model of passive systemic anaphylaxis, Cd300a–/–Cd300lf–/– mice showed lower rectal temperature than either Cd300a–/– or
Cd300lf–/– mice. Our results demonstrate the cooperativity of multiple inhibitory receptors expressed on MCs and their regulatory functions
upon binding to respective ligands.
Keywords: CD300a, CD300lf, ceramide, mast cells, phosphatidylserine

https://doi.org/10.1093/jimmun/vkae030