title: B Cell-Intrinsic IDO1 Regulates Humoral Immunity to T Cell-Independent Antigens.
abstract: Humoral responses to nonproteinaceous Ags (i.e., T cell independent [TI]) are a key component of the early response to bacterial and viral infection and a critical driver of systemic autoimmunity. However, mechanisms that regulate TI humoral immunity are poorly defined. In this study, we report that B cell-intrinsic induction of the tryptophan-catabolizing enzyme IDO1 is a key mechanism limiting TI Ab responses. When Ido1(-/-) mice were immunized with TI Ags, there was a significant increase in Ab titers and formation of extrafollicular Ab-secreting cells compared with controls. This effect was specific to TI Ags, as Ido1 disruption did not affect Ig production after immunization with protein Ags. The effect of IDO1 abrogation was confined to the B cell compartment, as adoptive transfer of Ido1(-/-) B cells to B cell-deficient mice was sufficient to replicate increased TI responses observed in Ido1(-/-) mice. Moreover, in vitro activation with TLR ligands or BCR crosslinking rapidly induced Ido1 expression and activity in purified B cells, and Ido1(-/-) B cells displayed enhanced proliferation and cell survival associated with increased Ig and cytokine production compared with wild-type B cells. Thus, our results demonstrate a novel, B cell-intrinsic, role for IDO1 as a regulator of humoral immunity that has implications for both vaccine design and prevention of autoimmunity.
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Rahul
authors.initials: R
authors.lastname: Shinde
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Michiko
authors.initials: M
authors.lastname: Shimoda
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Kapil
authors.initials: K
authors.lastname: Chaudhary
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Haiyun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Eslam
authors.initials: E
authors.lastname: Mohamed
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Jillian
authors.initials: J
authors.lastname: Bradley
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Sridhar
authors.initials: S
authors.lastname: Kandala
authors.affiliation: Cancer Signaling and Angiogenesis Programs, Cancer Center, Georgia Regents University, Augusta, GA 30912; and.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Cancer Signaling and Angiogenesis Programs, Cancer Center, Georgia Regents University, Augusta, GA 30912; and.
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance, Cancer Center, Georgia Regents University, Augusta, GA 30912; Division of Nephrology, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912 tmcgaha@gru.edu.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: McGaha
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D000955:Antigens, T-Independent / Q000276:immunology*; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D056724:Immunity, Humoral / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism
chemical_list: D000955:Antigens, T-Independent; C583637:IDO1 protein, mouse; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015850:Interleukin-6; D011947:Receptors, Antigen, B-Cell; D016753:Interleukin-10