T Cell–B Cell Thymic Cross-Talk: Maintenance and Function of Thymic B Cells Requires Cognate CD40–CD40 Ligand Interaction

Abstract

Thymic development requires bidirectional interaction or cross-talk between developing T cells and thymic stromal cells, a relationship that has been best characterized for the interaction between thymocytes and thymic epithelial cells (TECs). We have characterized here the requirement for similar cross-talk in the maintenance and function of thymic B cells, another population that plays a role in selection of developing thymic T cells. We found that maintenance of thymic B cells is strongly dependent upon the presence of mature single positive (SP) thymocytes and on the interactions of these T cells with specific antigen ligand. Maintenance of thymic B cell number is strongly dependent upon B cell-autonomous expression of CD40, but not MHCII, indicating that direct engagement of CD40 on thymic B cells is necessary to support their maintenance and proliferation. Thymic B cells can mediate negative selection of superantigen-specific self-reactive SP thymocytes, and we show that CD40 expression on B cells is critical for this negative selection. Cross-talk with thymic T cells is thus required to support the thymic B cell population through a pathway that requires cell-autonomous expression of CD40, and that reciprocally functions in negative selection of autoreactive T cells.

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

“…By contrast, an agonistic anti-CD40 antibody induced Airereporter expression and Aire mRNA transcription together with MHCII upregulation in B cells ( Figures 3A, 3B, and S3). In Cd40 -/-and Cd40lg -/-mice, thymic but not peripheral B cells were substantially diminished, consistent with CD40 signals controlling thymic B cell numbers ( Figure 3C; Fujihara et al, 2014). Most significantly, thymic B cells in these mice did not express Aire mRNA, had not undergone class-switching, and failed to upregulate CD80 ( Figures 3D-3F).…”

“…In addition to providing thymic B cells with enhanced APC features such as elevated MHCII and CD80, CD40 signaling was shown to also control the size of the thymic B cell pool, which in sum should quantitatively enhance the tolerogenic potential of the thymic B cell population as a whole (Fujihara et al, 2014). Importantly, our findings strongly suggest that besides these quantitative effects, intrathymic licensing is likely to have a substantial qualitative influence on the self antigen spectrum displayed by thymic B cells.…”

“…Plasmacytoid DCs were shown to import peripherally acquired antigens into the thymus and present these for central tolerance induction (Hadeiba et al, 2012). The thymus also contains B cells, whose capacity to act as APCs for central tolerance has been documented in the context of superantigens or B cell receptor (BCR)-mediated antigen capture and presentation, through B-cell-specific expression of a self-antigen or by selectively expressing major histocompatibility complex (MHC) molecules on B cells (Frommer and Waisman, 2010;Fujihara et al, 2014;Kleindienst et al, 2000;Perera et al, 2013). Recent evidence also suggests that thymic B cells might be involved in regulatory T cell induction (Walters et al, 2014).…”

Thymic B cells promote thymus-derived regulatory T cell development and proliferation

“…All data shown are representative of three independent experiments. ***p < 0.001. development, the maintenance of thymic B cells requires CD40/ CD40L but not MHC class II interaction [48]. Hence, signals required for thymic Treg cell development are distinct from those required for thymic B cell maintenance.…”

The development and function of thymic B cells

“…Additionally, it has been shown that CD40L −/− mice have a 10x reduction in the total number of thymic B cells, suggesting this pathway may be important for the survival and maintenance of thymic B cells [28]. More recently it was demonstrated by Fujihara et al that CD40 is important for thymic B cell proliferation and function in a cell autonomous manner [29]. …”