T cell receptor-independent CD4 signalling: CD4-MHC class II interactions regulate intracellular calcium and cyclic AMP.
CD4 is a coreceptor on T helper (Th) cells that interacts with MHC class II molecules (MHCII). The mechanisms mediating the effects of CD4 on responses by T helper cells to stimulation of the antigen-specific T cell receptor (TCR) are still poorly understood. Here, we demonstrate T cell costimulation via CD4 signalling independent of T cell receptor-mediated signals. Incubation of T helper cells with peptide mimetics of the CD4-binding region on the MHC class II beta2 domain caused intracellular calcium mobilization in the absence of antigen or other T cell receptor stimuli. Engagement of CD4 by peptide mimetics or wild-type MHC class II, but not by mutant MHC class II molecules incapable of engaging CD4, inhibited the T cell receptor-mediated increase in cyclic AMP (cAMP) concentrations in T helper cells. CD4-mediated signals activated cyclic AMP phosphodiesterases (PDEs) and inhibited adenylyl cyclase. Full activation and clonal expansion of antigen-stimulated T helper cells required the CD4-mediated regulation of cyclic AMP. Our results suggest a costimulatory mechanism of CD4 function that acts on the second messengers, calcium and cyclic AMP.
Zhou
Wenhong
W
Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555-1070, USA.
König
Rolf
R
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology*; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D018716:Molecular Mimicry / Q000276:immunology; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D015704:CD4 Antigens; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D000242:Cyclic AMP; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D000262:Adenylyl Cyclases