Immunology Letters 68 (1999) 3 – 15 Review Immunoreceptor tyrosine-based inhibition motif-bearing receptors regulate the immunoreceptor tyrosine-based activation motif-induced activation of immune competent cells Ja ´nos Gergely a, *, Israel Pecht b , Gabriella Sa ´rmay c a Research Group of the Hungarian Academy of Science at the Department of Immunology, Eo ¨to ¨s Lora ´nd Uniersity, H-2131 Go ¨d, Hungary b The Weizmann Institute of Science, 71 600 Rehoot, Israel c Department of Immunology, Eo ¨to ¨s Lora ´nd Uniersity, H-2131 Go ¨d, Hungary Abstract ITIM-bearing receptors, a family which only recently has been recognized, play a key role in the regulation of the ITAM-induced activation of immune competent cells. The mechanism of ITM-mediated regulation in various cells was recently clarified. The present review focuses on ITIM bearing membrane proteins that negatively regulate the activation of cells when co-crosslinked with ITAM containing receptors, illustrates the inhibitory processes by the negative regulation of B-, NK-, T-cells and mast cells and summarizes current views on the mechanism of ITIM-mediated inhibition. © 1999 Elsevier Science B.V. All rights reserved. Keywords: ITAM; ITIM; Immune competent cells 1. Introduction Antigen recognition and the communication among immune cells resulting in various forms of immune responses is mediated by membrane bound receptors, by the crosstalk of various receptors expressed on the same cell and by direct or indirect interaction(s) of the immunocompetent cells. Signal transduction by the multisubunit immune recognition receptors (MIRR) such as antigen receptors of T- and B-cells (TCR, BCR) and certain types of FcRs [1] is strictly dependent on a module located in the cytoplasmic part of the receptor subunit(s) termed immunoreceptor tyrosine-based acti- vation motif (ITAM) [2]. Experiments when only the same type of receptors are aggregated showed that the members of the MIRR family trigger similar activation pathways [3]. During the immune response, however, due to interactions with counter receptors on partner cells and/or co-crosslinking of various receptors on the same cell, in addition to the members of the MIRR family, several other receptors are affected in the same time. The involvement of other receptors (co-receptors) may alter both the quality and magnitude of the re- sponses induced by the MIRR receptors, e.g. the co- crosslinking of CR2 and BCR enhances [4], while that of BCR and FcRIIb inhibits the BCR-mediated acti- vation of B-cells [5]. The inhibition of BCR induced B-cell activation depends on a module located in the intracytoplasmic domain of the FcRIIb, termed im- munoreceptor tyrosine-based inhibition motif (ITIM) [6]. ITIMs have recently found to be expressed in an increasing number of transmembrane receptors, which suppress cell activation induced by ITAM bearing re- ceptors [7] and the ITIM-mediated inhibitory mecha- nism is widely used as a control mechanism of cellular function. * Corresponding author. Meyerhoff Visiting Professor at the Weiz- mann Institute of Science, 71600 Rehovot, Israel. 0165-2478/99/$ - see front matter © 1999 Elsevier Science B.V. All rights reserved. PII:S0165-2478(99)00024-3