ITIM

ITIM stands for immunoreceptor tyrosine-based inhibitory motif, a short conserved sequence located in the cytoplasmic tails of various immune receptors. ITIMs function as negative regulators of signaling by serving as docking sites for protein tyrosine phosphatases when phosphorylated, thereby dampening activation signals in immune cells.

Mechanistically, ITIMs are phosphorylated on a key tyrosine residue by Src family kinases following receptor engagement. The phosphorylated ITIM recruits phosphatases such as SHP-1 (PTPN6), SHP-2 (PTPN11), or SHIP (INPP5D) through SH2 domain interactions. The recruited phosphatases dephosphorylate downstream signaling components, counteracting signals from activating receptors and reducing cellular responses. Some receptors harbor more than one ITIM, allowing recruitment of multiple phosphatases or modulating the strength and duration of inhibition.

Examples of ITIM-containing receptors include FcγRIIb, LAIR-1, members of the LILR/LILRB family, CD22, and CD72, as well as PECAM-1. These receptors are expressed on B cells, NK cells, macrophages, and other leukocytes, and they help maintain self-tolerance and prevent excessive inflammation by tempering activation through various signaling pathways.

Biological significance and interplay with ITAMs: ITIMs balance immune activation by opposing immunoreceptor tyrosine-based activation motifs (ITAMs). This balance influences processes such as B cell tolerance, NK cell education, and the regulation of inflammatory responses. Dysregulation of ITIM-mediated inhibition can contribute to autoimmunity or impairment of immune responses, making ITIMs a focus of research in immunology and therapeutic intervention.