title: IDO2 Modulates T Cell-Dependent Autoimmune Responses through a B Cell-Intrinsic Mechanism.
abstract: Mechanistic insight into how adaptive immune responses are modified along the self-nonself continuum may offer more effective opportunities to treat autoimmune disease, cancer, and other sterile inflammatory disorders. Recent genetic studies in the KRN mouse model of rheumatoid arthritis demonstrate that the immunomodulatory molecule IDO2 modifies responses to self-antigens; however, the mechanisms involved are obscure. In this study, we show that IDO2 exerts a critical function in B cells to support the generation of autoimmunity. In experiments with IDO2-deficient mice, adoptive transplant experiments demonstrated that IDO2 expression in B cells was both necessary and sufficient to support robust arthritis development. IDO2 function in B cells was contingent on a cognate, Ag-specific interaction to exert its immunomodulatory effects on arthritis development. We confirmed a similar requirement in an established model of contact hypersensitivity, in which IDO2-expressing B cells are required for a robust inflammatory response. Mechanistic investigations showed that IDO2-deficient B cells lacked the ability to upregulate the costimulatory marker CD40, suggesting IDO2 acts at the T-B cell interface to modulate the potency of T cell help needed to promote autoantibody production. Overall, our findings revealed that IDO2 expression by B cells modulates autoimmune responses by supporting the cross talk between autoreactive T and B cells.
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096;
authors.forename: Lauren M F
authors.initials: LM
authors.lastname: Merlo
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096;
authors.forename: James B
authors.identifier: 0000-0001-8136-1999
authors.initials: JB
authors.lastname: DuHadaway
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096;
authors.forename: Samantha
authors.initials: S
authors.lastname: Grabler
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096; Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107; and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096; Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107; and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Muller
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096; mandik-nayakl@mlhs.org.
authors.forename: Laura
authors.initials: L
authors.lastname: Mandik-Nayak
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C586429:IDO2 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase