Thymic B Cells Are Licensed to Present Self Antigens for Central T Cell Tolerance Induction

Abstract

Thymic antigen-presenting cells (APCs) such as dendritic cells and medullary thymic epithelial cells (mTECs) use distinct strategies of self-antigen expression and presentation to mediate central tolerance. The thymus also harbors B cells; whether they also display unique tolerogenic features and how they genealogically relate to peripheral B cells is unclear. Here, we found that Aire is expressed in thymic but not peripheral B cells. Aire expression in thymic B cells coincided with major histocompatibility class II (MHCII) and CD80 upregulation and immunoglobulin class-switching. These features were recapitulated upon immigration of naive peripheral B cells into the thymus, whereby this intrathymic licensing required CD40 signaling in the context of cognate interactions with autoreactive CD4(+) thymocytes. Moreover, a licensing-dependent neo-antigen selectively upregulated in immigrating B cells mediated negative selection through direct presentation. Thus, autoreactivity within the nascent T cell repertoire fuels a feed forward loop that endows thymic B cells with tolerogenic features.

Prédisposition aux pathologies auto-immmunes

“…L'expression de AIRE est exclusivement retrouvée dans certains types cellulaires comme les CETm [3], les cellules B thymiques [11], les monocytes [12] et les cellules hépatiques foetales [13]. Plusieurs études ont permis d'appréhender les mécanismes de contrôle basal de l'expression de AIRE dans les CETm.…”

The Human Thymus Is Enriched for Autoreactive B Cells

“…These are located in the medulla and create rosette-like structures surrounded by T cells (10,11). It has been suggested that these B cells are involved in autoantigen presentation to T cells (12)(13)(14)(15). B cells express high levels of MHC-II and can efficiently present Ags that they recognize with their surface Igs (16).…”

“…B cell subsets were purified from homogenized pediatric thymuses, fetal limb BM suspensions, and pediatric BM aspirates as described previously (11,(19)(20)(21)(22) (17,23,24), Ig cloning, and Ab expression procedures were performed as described previously (15,17,23,24). The usage of V, D, and J genes as well as the junctional regions were analyzed using the international ImMunoGeneTics information system (http://www.imgt.org/) (25).…”

“…Ab reactivity analysis was performed as described previously, and the highly polyreactive ED38 Ab was used as positive control (15,17,23,24). Briefly, ELISA assays were performed to determine Ig reactivity to HEp-2 cell lysate (Inova Diagnostics), HEp-2 cell protein lysate (Novus Biologicals), dsDNA, insulin, LPS, BSA (all from Sigma-Aldrich), and malondialdehyde (MDA)-BSA (Academy Biomedical) using Ab concentrations of 10 mg/ml (HEp-2 cell lysate and HEp-2 cell protein lysate) or 1 mg/ml (dsDNA, insulin, LPS, BSA, and MDA-BSA).…”

A highly conserved NF‐κB‐responsive enhancer is critical for thymic expression of Aire in mice

“…In contrast to medullary thymic epithelial cell with low expression of MHC class II (mTEC lo ), which expresses relatively low levels of MHCII, costimulatory molecules, and TSAs, the Aire + mTEC hi population has a broad TSA-expression profile and a high antigen-presenting capacity, which makes these cells well suited to mediate negative selection. Aside from the mTEC hi population, Aire is expressed in thymic B cells, as well as in a rare subtype of antigen-presenting cells in the spleen and lymph nodes, and in the germ cells in the testis [19][20][21][22][23]. mTEC maturation into the mTEC hi population and Aire expression are developmentally sequential events, both dependent on acquiring and maintaining responsiveness to signaling through the TNFR family member receptor activator of nuclear factor κB (RANK) selectively expressed in the thymus by the mTECs [24,25].…”