Jiménez-Fernández, Maríade la Fuente, HortensiaMartín, PilarCibrián, DanaySánchez-Madrid, Francisco2024-12-042024-12-042023EXCLI J. 2023 Mar 16:22:334-351.https://hdl.handle.net/20.500.12105/25860This work was supported by grant P2022/BMD7209-INTEGRAMUNE from the Comunidad de Madrid to FS-M and PM, a grant from “La Caixa” Banking Foundation (HR17-00016) to FS-M; the Spanish Ministerio de Ciencia e Innovación (PDC2021-121719-I00 and PID-2020-120412RB-I00 to FS-M); and grants from the Instituto de Salud Carlos III (PI21/01583 to HF; PI22/01842 to DC; and PI22/01759 to PM). M. Jiménez-Fernández is supported by Formación de Personal Investigador Severo Ochoa (FPI-SO) Program (PRE2019-087941). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV2015-0505).CD69 is an early leukocyte activation marker involved in the regulation of the immune response. Initial studies evaluated its function using monoclonal antibodies until knock-out mice were developed. Subsequently, four ligands for CD69 have been identified, namely galectin-1, S100A8/S100A9 complex, myosin light chains 9 and 12, and oxidized low-density lipoproteins. In addition, several molecules are laterally associated with and regulated by CD69, including calreticulin and two transmembrane receptors, sphingosine-1-phosphate receptor (S1P1) and the heterodimeric amino acid transporter complex SLC7A5-SLC3A2 (LAT1-CD98). Recently, CD69 engagement has been shown to induce the expression of the immunoregulatory receptor programmed cell death-1 (PD-1) in T cells. The molecular signaling induced by CD69 has been explored in different scenarios and cell types. This review provides a perspective on the molecular pathways, ligands and cellular functions known to be regulated by CD69.engVoRhttp://creativecommons.org/licenses/by/4.0/CD69CD69-ligandsCD69-signalingmolecular signaling-pathwayAttribution 4.0 International37223078Experimental and Clinical Sciences Journalopen access