Sweet, RebeccaOls, Michael L.Cullen, JMilam, Ashley V.Yagita, HideoShlomchik, M J2015-12-100027-8424http://hdl.handle.net/1885/50100Extrafollicular (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 Bcell 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 isotypeswitch 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.Author/s retain copyrightKeywords: autoantibody; B lymphocyte receptor; CD40 ligand; interleukin 21; rheumatoid factor; toll like receptor; animal cell; animal experiment; antibody production; article; autoimmunity; B lymphocyte; cell interaction; cell isolation; cell stimulation; controll Autoantibodies; Systemic lupus201110.1073/pnas.10185711082016-02-24