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 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.systemic lupus | autoantibodies

Artery Tertiary Lymphoid Organs Contribute to Innate and Adaptive Immune Responses in Advanced Mouse Atherosclerosis

“…87,88,107 Third, immune complexes with unprocessed antigen can gain access to TLOs and bind to follicular DCs within germinal centers at higher concentrations when compared with follicular DCs of the more distant germinal centers of SLOs. 19,47,105,[107][108][109][110][111][112][113] Fourth, TLOs may be shielded from the centralized immune system because they may mount primary immune responses within territorialized tissue environments, whereas LNs and spleen drain large terrains (Figure 4). Fifth, antigen-specific T and B lymphocytes generated in TLOs may not only be activated, proliferate, and undergo avidity maturation, and affinity maturation, respectively, but also receive socalled imprinting signals to home specifically to the target tissue that originally accommodated the antigen during the primary immune response.…”

Autoreactive helper T cells alleviate the need for intrinsic TLR signaling in autoreactive B cell activation

“…AM14 Vκ8R, AM14 Vκ8R Tlr7 -/-, AM14 Vκ8R Tlr9 -/-, and AM14 Vκ8R Tlr7/9 -/-mice were described previously (10,19,45,46). DO11.10 Tcrα -/-BALB/c mice were previously described (18). Rag2 -/-BALB/c mice were from Jackson Laboratories.…”

“…13C2 and 1B9 T cells were also positively selected into the CD4 compartment on a nontransgenic BALB/c background (data not shown). However, we proceeded with DO11.10 Tcrα -/-BALB/c mice as bone marrow recipients for retrogenic mice, because they enabled us to use V-specific antibodies to distinguish the T cell clones of interest and prevented any complications from contaminating endogenous BALB/c T cells, which have been shown to help the AM14 B cell response (18).…”

“…AM14 B cells proliferate in response to both PL2-3 and BWR4 in the absence of T cells (18,25). To assess whether primary …”

“…Previous work in the lab indicated that cognate helper T cells for AM14 B cells exist in the repertoire of BALB/c mice (18).…”