title: Differences in CD44 Surface Expression Levels and Function Discriminates IL-17 and IFN-γ Producing Helper T Cells.
abstract: CD44 is a prominent activation marker which distinguishes memory and effector T cells from their naïve counterparts. It also plays a role in early T cell signaling events as it is bound to the lymphocyte-specific protein kinase and thereby enhances T cell receptor signalling. Here, we investigated whether IFN-γ and IL-17 producing T helper cells differ in their CD44 expression and their dependence of CD44 for differentiation. Stimulation of CD4+ T cells with allogeneic dendritic cells resulted in the formation of three distinguishable populations: CD44+, CD44++ and CD44+++. In vitro and in vivo generated allo-reactive IL-17 producing T helper cells were mainly CD44+++ as compared to IFN-γ+ T helper cells, which were CD44++. This effect was enhanced under polarizing conditions. T helper 17 polarization led to a shift towards the CD44+++ population, whereas T helper 1 polarization diminished this population. Furthermore, blocking CD44 decreased IL-17 secretion, while IFN-γ was barely affected. Titration experiments revealed that low T cell receptor and CD28 stimulation supported T helper 17 rather than T helper 1 development. Under these conditions CD44 could act as a co-stimulatory molecule and replace CD28. Indeed, rested CD44+++CD4+ T cells contained already more total and especially phosphorylated zeta-chain-associated protein kinase 70 as compared to CD44++ cells. Our results support the notion, that CD44 enhances T cell receptor signaling strength by delivering lymphocyte-specific protein kinase, which is required for induction of IL-17 producing T helper cells.
authors.affiliation: Institute of Medical Immunology, Charité University Medicine, Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schumann
authors.affiliation: Institute of Medical Immunology, Charité University Medicine, Berlin, Germany.
authors.forename: Katarina
authors.initials: K
authors.lastname: Stanko
authors.affiliation: Institute of Medical Immunology, Charité University Medicine, Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schliesser
authors.affiliation: Institute of Medical Immunology, Charité University Medicine, Berlin, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Appelt
authors.affiliation: Institute of Medical Immunology, Charité University Medicine, Berlin, Germany; Berlin Brandenburg Center for Regenerative Therapies, Charité University Medicine, Berlin, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000096:biosynthesis*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D018960:Hyaluronan Receptors; D020381:Interleukin-17; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma