title: ICOS expression by activated human Th cells is enhanced by IL-12 and IL-23: increased ICOS expression enhances the effector function of both Th1 and Th2 cells.
abstract: Previous mouse studies have shown that IL-4 increases the expression of ICOS on activated Th cells, resulting in enhanced ICOS expression on Th2 cells. In this study, we show that ICOS expression on human Th cells is not increased by IL-4, but by IL-12 and by IL-23 instead. Consequently, ICOS expression during IL-12-driven Th1 cell polarization was transiently increased compared with the levels on Th0 cells and IL-4-driven Th2 cells. Addition of IL-12 and/or IL-23 during restimulation increased ICOS expression to the same extent on pre-established Th1, Th2, and Th0 cells, indicating that ICOS levels are not stably imposed by prior polarization. In contrast to the findings in the mouse, IL-4 significantly suppressed the ICOS-enhancing effects of IL-12 and IL-23. The functional consequence of variable ICOS levels was shown in coculture experiments with cells expressing the ICOS-ligand B7-related protein 1 (either transfected Chinese hamster ovary cells or autologous dendritic cells). Ligation of ICOS on 2-day-preactivated effector cells increased their cytokine production to an extent proportional to their ICOS expression levels. As the ICOS-enhancing potentials of IL-12 and IL-23 were maintained for several days after stimulation, both on Th1 and Th2 cells, we propose the concept that local regulation of ICOS expression on activated Th cells by IL-12 and/or IL-23 may provide a powerful means to amplify effector T cell responses in peripheral tissues, independently of the polarized state of the Th cells.
authors.affiliation: Academic Medical Center, Department of Cell Biology and Histology, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Lianne
authors.initials: L
authors.lastname: Wassink
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Vieira
authors.forename: Hermelijn H
authors.initials: HH
authors.lastname: Smits
authors.forename: Gillian A
authors.initials: GA
authors.lastname: Kingsbury
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: Martien L
authors.initials: ML
authors.lastname: Kapsenberg
authors.forename: Eddy A
authors.initials: EA
authors.lastname: Wierenga
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D016466:CHO Cells; D018920:Coculture Techniques; D006224:Cricetinae; D003412:Cricetulus; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D015847:Interleukin-4 / Q000494:pharmacology; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D011993:Recombinant Fusion Proteins / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D013045:Species Specificity; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; C556692:ICOS protein, human; C508840:IL23A protein, human; C556694:Icos protein, mouse; C508841:Il23a protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D018664:Interleukin-12; D015847:Interleukin-4