title: In vivo anti-LAP mAb enhances IL-17/IFN-γ responses and abrogates anti-CD3-induced oral tolerance.
abstract: Regulatory T cells (Tregs) play a critical role in the maintenance of immunological tolerance. The best-characterized Tregs are those expressing the transcription factor Foxp3 and in vivo modulation of Foxp3 Tregs has been employed to study their role in immune homeostasis. Latency-associated peptide (LAP) is a membrane-bound TGF-β complex that has also been shown to play a role in Treg function and oral tolerance. We developed a novel anti-mouse LAP mAb that allowed us to investigate the effect of targeting LAP in vivo on immune function and on anti-CD3-induced oral tolerance. We found that in vivo anti-LAP mAb administration led to a decrease in the number of CD4+LAP+ Tregs in spleen and lymph nodes without affecting CD4+Foxp3+ Tregs. Spleen cells from anti-LAP-injected mice proliferated more in vitro and produced increased amounts of IL-2, IL-17 and IFN-γ. Moreover, injection of anti-LAP antibody abrogated the protective effect of oral anti-CD3 on experimental autoimmune encephalomyelitis (EAE). Finally, in vivo anti-LAP administration prior to myelin oligodendrocyte glycoprotein immunization resulted in severe EAE in the absence of pertussis toxin, which is used for EAE induction. Our findings demonstrate the importance of CD4+LAP+ T cells in the control of immune homeostasis and autoimmunity and provides a new tool for the in vivo investigation of murine LAP+ Tregs on immune function.
authors.affiliation: Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Andre P
authors.initials: AP
authors.lastname: da Cunha
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Henry Y
authors.initials: HY
authors.lastname: Wu
authors.affiliation: Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rafael M
authors.initials: RM
authors.lastname: Rezende
authors.affiliation: Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Vandeventer
authors.affiliation: Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA The Partners Multiple Sclerosis Center, 1 Brookline Place, Brookline, MA 02445, USA hweiner@rics.bwh.harvard.edu.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D007108:Immune Tolerance / Q000187:drug effects*; D007371:Interferon-gamma / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D017252:CD3 Complex; D020381:Interleukin-17; D010455:Peptides; D007371:Interferon-gamma
keywords: TGF-beta; experimental autoimmune encephalomyelitis; inflammation; latency-associated peptide; regulatory T cells