Edited by: Geraldo Aleixo Passos, University of São Paulo, Brazil
Reviewed by: Ari Waisman, Johannes-Gutenberg University of Mainz, Germany; Olga Ucar, German Cancer Research Center, Germany
Specialty section: This article was submitted to Immunological Tolerance, a section of the journal Frontiers in Immunology
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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.
B cells represent approximately 0.3% of the thymic cellularity. Although their absolute number may, in fact, exceed that of thymic dendritic cells, their role a APCs for central tolerance induction is not well understood, and thymic B cells have often been regarded as “innocent bystanders.” Recent data suggest that this view may need to be revised. Here, we will provide a short overview of novel insights into distinct features of thymic B cells and how these may predispose thymic B cells to support T cell tolerance.
The early thymic progenitor (ETP), i.e., the cell type that gives rise to the T cell lineage, retains some B cell potential (
Does intrathymic B cell differentiation occur under non-perturbed
Using more conclusive surface marker combinations, we recently revisited the issue whether the thymus harbors significant numbers of B cell precursors (
Taken together, it is reasonable to assume that both intrathymic B lymphopoesis and immigration of BM-derived B cells contribute to the thymic B cell pool. However, we lack a precise understanding of the relative contribution of either pathway. On the one hand, the virtual absence of pro- and pre-B cells may render intrathymic differentiation an unlikely source of the majority of thymic B cells. On the other hand, thymic B cells in parabiosed mice do not equilibrate to the same extent as is observed for splenic B cells, insinuating a substantial contribution of intrathymic B cell differentiation (
Some phenotypic features (e.g., CD5 expression) had suggested that thymic B cells may be related to the fetal liver-derived B1 lineage (
Unlike resting B cells in spleen and lymph node, thymic B cells express high levels of MHC class II and the co-stimulatory molecules CD80 and CD86 (
Are these distinctive features of thymic B cells an inherent feature of B cells that arise through intrathymic B lympopoiesis? To address this question, we followed the fate of i.v. injected IgM+IgD+ B cells, which are MHCIIintermediate, CD80− and Aire−. Seven days after injection, donor cells in the spleen had retained their initial phenotype. In contrast, cells that had immigrated into the thymus recapitulated all features of
The transition from a MHCIIintCD80−Aire−stage to a MHCIIhiCD80+Aire+ phenotype during thymic B cell licensing is strikingly reminiscent of mTEC “maturation.” However, whereas mTEC maturation is orchestrated by RANK signals (
Fujihara et al. showed that thymic B cell numbers are regulated by CD4 single-positive (SP) thymocytes (
Several studies have shown that thymic B cells can contribute to negative selection under particular experimental conditions. Forced expression of the I-E MHCII molecule exclusively on B cells led to deletion of superantigen reactive T cells (
What is known about the overall contribution of thymic B cells to central T cell tolerance? In mice lacking B cells, the size of the CD4SP cell compartment is significantly increased (
The role of CD40 and the cognate interactions between B cells and CD4 T cells during thymic B cell licensing are reminiscent of the germinal center (GC) reaction (
B cells efficiently present antigens that have been captured via the BCR (
As a consequence of licensing, thymic B cells class-switch to IgG or IgA. It is therefore conceivable that thymic B cells present B lineage-specific “neo-epitopes” generated through isotype-class-switching or possibly also somatic hypermutation. In all likelihood, and in distinction from the GC reaction, class-switching in the thymus may occur “spontaneously,” i.e., independent of cognate help downstream of BCR-mediated antigen capture. This has obvious implications for the emergence of “natural” Igs. Some thymic B cells display a memory B cell phenotype (CD38+Faslo), and it is possible that IgG- or IgA-positive thymic B cells re-enter the blood stream. In fact, we observed a minute population of class-switched donor cell in the periphery after intrathymic injection of naive B cells (Tomoyoshi Yamano and Ludger Klein unpublished). More work is needed to clarify the role of the thymus as a potential source of natural Igs.
It was shown that thymic B cells express Ltα and Ltβ, and thereby regulate mTEC cellularity (
The presence of B cells with an “activated” phenotype in the healthy human thymus has long been recognized (
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by the Deutsche Forschungsgemeinschaft (KL 1228/5-1). TY was supported by a Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship.