CD99L2 (CD99 molecule like 2) is a highly conserved type I transmembrane protein that functions as a homophilic adhesion molecule with critical roles in both immune cell trafficking and neuronal function 1. In leukocyte biology, CD99L2 plays a key role in transendothelial migration by helping leukocytes overcome the endothelial basement membrane during extravasation 23. It functions independently of but at the same anatomical site as PECAM-1, regulating a specific sequential step in transmigration between PECAM and CD99 3. CD99L2 promotes this process by recruiting the lateral border recycling compartment to transmigration sites 3. Beyond immune function, CD99L2 exhibits high neuronal expression and regulates excitatory synapse development, neurite outgrowth, and restrains immediate-early gene activation by inhibiting CREB and SRF transcription factors 4. Loss-of-function variants cause X-linked spastic ataxia through impaired CAPN1 protease activation and synaptic dysfunction 5. The protein serves as an activating interactor of calcium-dependent protease CAPN1, with cellular mislocalization disrupting this interaction 5. CD99L2's evolutionary conservation across species suggests essential biological functions 1.