title: Facultative role for T cells in extrafollicular Toll-like receptor-dependent autoreactive B-cell responses in vivo.
abstract: Extrafollicular (EF) B-cell responses are increasingly being recognized as an alternative pathway of B-cell activation, particularly in autoimmunity. Critical cellular interactions required for the EF B-cell response are unclear. A key question in autoimmunity, in which Toll-like receptor (TLR) signals are costimulatory and could be sufficient for B-cell activation, is whether T cells are required for the response. This is pivotal, because autoreactive B cells are considered antigen-presenting cells for autoreactive T cells, but where such interactions occur has not been identified. Here, using AM14 site-directed transgenic rheumatoid factor (RF) mice, we report that B cells can be activated, differentiate, and isotype-switch independent of antigen-specific T-cell help, αβ T cells, CD40L signaling, and IL-21 signaling to B cells. However, T cells do dramatically enhance the response, and this occurs via CD40L and IL-21 signals. Surprisingly, the response is completely inducible T-cell costimulator ligand independent. These results establish that, although not required, T cells substantially amplify EF autoantibody production and thereby implicate T-independent autoreactive B cells as a potential vector for breaking T-cell tolerance. We suggest that these findings explain why autoreactivity first focuses on self-components for which B cells carry TLR ligands, because these will uniquely be able to activate B cells independently of T cells, with subsequent T-B interactions activating autoreactive T cells, resulting in chronic autoimmunity.
authors.affiliation: Department of Immunobiology and Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Sweet
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Ols
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Cullen
authors.forename: Ashley Viehmann
authors.initials: AV
authors.lastname: Milam
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation / Q000276:immunology; D008231:Lymphopenia / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics; D012217:Rheumatoid Factor / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D008024:Ligands; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051193:Toll-Like Receptors; D012217:Rheumatoid Factor