APMIS 107: 887-95. 1999 Cor,vriaht 0 APMIS 1999 Printed in Denmark . AN rights reserved MPUU8 ISSN 0903-4641 Signal transduction by the ma-jorhistocompatibility comdex class I molecule Re view ar tide ANDERS E. PEDERSEN, S0REN SKOV, S0REN BREGENHOLT, MORTEN RUHWALD and MOGENS H. CLAESSON Laboratory of Experimental Immunology, Department of Medical Anatomy, The Panum Institute, The University of Copenhagen, Copenhagen, Denmark Pedersen AE, Skov S, Bregenholt S, Ruhwald M & Claesson MH. Signal transduction by the major histocompatibility complex class 1 molecule. APMIS 1999;107:887-95. Ligation of cell surface major histocompatibility class I (MHC-I) proteins by antibodies, or by their native counter receptor, the CD8 molecule, mediates transduction of signals into the cells. MHC-I- mediated signaling can lead to both increased and decreased activity of the MHC-I-expressing cell depending on the fine specificity of the anti-MHC-I antibodies, the context of CD8 ligation, the nature and cell cycle state of the MHC-I-expressing cell and the presence or absence of additional cellular or humoral stimulation. This paper reviews the biochemical, physiological and cellular events immediately after and at later intervals following MHC-I ligation. It is hypothesized that MHC-I expression, both ontogenically and in evolution, is driven by a cell-mediated selection pressure advan- tageous to the MHC-I-expressing cell. Accordingly, in addition to their role in T-cell selection and functioning, MHC-I molecules might be of importance for the maintenance of cellular homeostasis not only within the immune system, but also in the interplay between the immune system and other organ systems. Key words: MHC-I; signals; lymphocytes. M. H. Claesson, Laboratory of Experimental Immunology, The Department of Medical Anatomy, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. The MHC complex and proteins The major histocompatibility complex (MHC), HLA and H-2 in man and mouse, respectively, Abbreviations: p2m, P2-microglobulin; BCR, B-cell antigen recep- tor; CTL: cytotoxic T lymphocytes; DAG, diacylgly- cerol; Ig, immunoglobulin; IP3, inositol triphosphate; IR, insulin receptor; JAK, Janus tyrosine kinase; JNK, June N-terminal kinase; MHC-I, major histo- compatibility complex class I; mAb, monoclonal antibody; NK, natural killer; NF, nuclear factor; PIP2, phosphoinositolbiphosphate; PI-3, phospho- inositide-3; PKC, protein kinase C; PLC, phos- pholipase C; STAT, signal transducers and activators of transcription: TCR, T-cell antigen receptor. is a group of genes which encodes a number of surface proteins that function as restriction elements for T lymphocytes, allowing them to recognize foreign as opposed to self antigens (1). Three classes of proteins, class I, I1 and 111, are encoded by the MHC locus. MHC class I (MHC-I) proteins, which are the topic of the present review, are expressed on the surface of nearly all nucleated cells. The MHC-I protein is a highly polymorphic, membrane-spanning heterotrimeric complex. It is composed of a heavy chain (3948 kDa) which is non-cova- lently linked to a 12 kDa light chain, beta2- microglobulin @2m) and an 8-12 residue pep- tide derived by proteolytical cleavage of cytosol- 887