ABSTRACT
The autoimmune regulator (Aire) serves an essential function for T cell tolerance by promoting the "promiscuous" expression of tissue antigens in thymic epithelial cells. Aire is also detected in rare cells in peripheral lymphoid organs, but the identity of these cells is poorly understood. Here, we report that Aire protein-expressing cells in lymph nodes exhibit typical group 3 innate lymphoid cell (ILC3) characteristics such as lymphoid morphology, absence of "classical" hematopoietic lineage markers, and dependence on RORγt. Aire+ cells are more frequent among lineage-negative RORγt+ cells of peripheral lymph nodes as compared with mucosa-draining lymph nodes, display a unique Aire-dependent transcriptional signature, express high surface levels of MHCII and costimulatory molecules, and efficiently present an endogenously expressed model antigen to CD4+ T cells. These findings define a novel type of ILC3-like cells with potent APC features, suggesting that these cells serve a function in the control of T cell responses.
Subject(s)
Antigen-Presenting Cells/immunology , Lymph Nodes/cytology , Lymphocytes/immunology , Lymphocytes/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Animals , CD11 Antigens/metabolism , Epithelial Cell Adhesion Molecule/metabolism , Gene Expression Regulation , Histocompatibility Antigens Class II/metabolism , Immunity, Innate , Mice , Mice, Inbred BALB C , Mice, Knockout , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Phenotype , Transcription, Genetic , AIRE ProteinABSTRACT
We show that latently gammaherpesvirus-infected B cells are present in the thymus. This could result in a functional T-cell tolerance against certain viral epitopes. It is conceivable that also antigens from other viruses or pathogens may be conveyed to the thymus for their immune evasion.
Subject(s)
B-Lymphocytes/immunology , Herpesviridae Infections/immunology , Immune Evasion , Immune Tolerance , Rhadinovirus/immunology , Thymus Gland/immunology , Animals , B-Lymphocytes/pathology , Herpesviridae Infections/pathology , Mice , Thymus Gland/pathologyABSTRACT
Central T cell tolerance is believed to be mainly induced by thymic dendritic cells and medullary thymic epithelial cells. The thymus also harbors substantial numbers of B cells. These may arise though intrathymic B lymphopoiesis or immigration from the bloodstream. Importantly, and in contrast to resting "mainstream" B cells in the periphery, thymic B cells display elevated levels of MHC class II and constitutively express CD80. Arguably, their most unexpected feature is the expression of autoimmune regulator. These unique features of thymic B cells result from a licensing process that involves cross-talk with CD4 single-positive T cells and CD40 signaling. Together, these recent findings suggest that B cells play a more prominent role as thymic APCs than previously appreciated.
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.
