title: CD28 ligation in the absence of TCR stimulation up-regulates IL-17A and pro-inflammatory cytokines in relapsing-remitting multiple sclerosis T lymphocytes.
abstract: CD28 is a crucial costimulatory receptor necessary full T cell activation. The role of CD28 in multiple sclerosis (MS) has been evaluated as the source of costimulatory signals integrating those delivered by TCR. However, CD28 is also able to act as a unique signaling receptor and to deliver TCR-independent autonomous signals, which regulate the expression and production of pro-inflammatory cytokines and chemokines. By comparing the cytokine/chemokine profiles of CD4(+) T cells from relapsing-remitting multiple sclerosis (RRMS) patients and healthy donors (HD), we found that CD28 engagement without TCR strongly up-regulates IL-8 and IL-6 expression in RRMS compared to HD. More interestingly, in RRMS but not in HD, CD28 stimulation selectively induces the expression of IL-17A by cooperating with IL-6-mediated signals. By using specific inhibitory drugs, we also identify the phosphatidylinositol 3 kinase (PI3K) as the critical regulator of CD28 proinflammatory functions in MS.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Biology and Biotechnology Charles Darwin, Sapienza University, Via dei sardi 70, 00185 Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Camperio
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Biology and Biotechnology Charles Darwin, Sapienza University, Via dei sardi 70, 00185 Rome, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Muscolini
authors.affiliation: Neuroimmunology Unit, IRCCS Santa Lucia Foundation, 00179 Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Volpe
authors.affiliation: Neuroimmunology Unit, IRCCS Santa Lucia Foundation, 00179 Rome, Italy.
authors.forename: Diletta
authors.initials: D
authors.lastname: Di Mitri
authors.affiliation: Neurology and Center for Experimental Neurological Therapies (CENTERS), S. Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy.
authors.forename: Rosella
authors.initials: R
authors.lastname: Mechelli
authors.affiliation: Neurology and Center for Experimental Neurological Therapies (CENTERS), S. Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Buscarinu
authors.affiliation: Department of Neurosciences, S. Camillo/Forlanini Hospital, 00151 Rome, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Ruggieri
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Biology and Biotechnology Charles Darwin, Sapienza University, Via dei sardi 70, 00185 Rome, Italy.
authors.forename: Enza
authors.initials: E
authors.lastname: Piccolella
authors.affiliation: Neurology and Center for Experimental Neurological Therapies (CENTERS), S. Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Salvetti
authors.affiliation: Department of Neurosciences, S. Camillo/Forlanini Hospital, 00151 Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Gasperini
authors.affiliation: Neuroimmunology Unit, IRCCS Santa Lucia Foundation, 00179 Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Biology and Biotechnology Charles Darwin, Sapienza University, Via dei sardi 70, 00185 Rome, Italy. Electronic address: loretta.tuosto@uniroma1.it.
authors.forename: Loretta
authors.initials: L
authors.lastname: Tuosto
mesh_terms: D000328:Adult; D000818:Animals; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002867:Chromones / Q000494:pharmacology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007739:L Cells; D008297:Male; D051379:Mice; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D002867:Chromones; D018836:Inflammation Mediators; D020381:Interleukin-17; D015850:Interleukin-6; D016209:Interleukin-8; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011948:Receptors, Antigen, T-Cell; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: Costimulation: Multiple sclerosis; Inflammation: Th17 cells; PI3K