B Cells: Mediators of Central Tolerance

RESEARCH HIGHLIGHTS

The deletion of self-reactive T cells expression pattern of AIRE in the BCR signalling in conjunction with during thymocyte development thymus, the authors noted a non- CD40 ligation suppressed AIRE (a process termed central tolerance) epithelial AIRE+ cell population, the upregulation, which may explain why is thought to be mediated mainly majority of which also expressed B cells in germinal centres (which by medullary thymic epithelial cells the B cell marker CD19. Further receive both BCR and CD40 signals) (mTECs) and dendritic cells (DCs) analysis confirmed their B cell do not express AIRE. However, the via distinct mechanisms. Reporting identity and showed that only thymic upregulation of MHC class II expres- in Immunity, Klein and colleagues B cells that B cells, and not peripheral B cells, sion and immunoglobulin class now show that B cells can also migrate into expressed AIRE. Thymic B cells were switching was AIRE dependent, sug- mediate central tolerance following also MHC class IIhiCD80+ and had gesting that AIRE influences thymic ‘licensing’ by thymocytes. the thymus undergone class switching. These B cell licensing in a cell-intrinsic, mTECs express the autoimmune are licensed thymic B cells expressed some AIRE- feedforward manner. regulator (AIRE) protein — which, through dependent transcripts, although they Finally, using various experimen- in addition to other functions, medi- were not enriched for TRAs. tal approaches with transgenic mice ates the promiscuous expression of CD40 ligation The phenotypic characteristics expressing haemagglutinin (HA) tissue-restricted antigens (TRAs) — by CD4 SP of thymic B cells were shown to under the control of Aire, the authors and directly present TRAs for T cell thymocytes emerge following the migration of showed that thymic B cells, but not tolerance induction. By contrast, to mediate mature peripheral B cells into the peripheral B cells, can directly present DCs acquire self-antigens from thymus and were dependent on an endogenous self-antigen (HA), the serum or the periphery, or by T cell central ligation of CD40 by CD4 single- the expression of which is induced ‘handover’ from mTECs, to mediate tolerance positive (SP) thymocytes; the authors upon thymic B cell licensing, and central tolerance. While assessing the referred to this microenvironmental can promote the negative selection of reprogramming as thymic B cell HA-specific CD4 SP thymocytes. licensing. Adoptively transferred These data show that B cells that MHC class II-deficient B cells migrate into the thymus are licensed failed to upregulate AIRE follow- through CD40 ligation by CD4 SP ing entry into the thymus, which thymocytes to mediate T cell central suggests that thymic B cell licens- tolerance through the direct pres- ing requires CD40 signals in the entation of a licensing-dependent context of MHC class II-restricted endogenous self-antigen. However, cognate B cell–CD4 SP thymocyte the exact nature of the self-antigens interactions. remains to be determined. B cells are extremely efficient at Olive Leavy presenting antigen that has been taken up by the B cell receptor ORIGINAL RESEARCH PAPER Yamano, T. et al. Thymic B cells are licensed to present self antigens (BCR), and therefore it is possible for central T cell tolerance induction. Immunity S.Bradbrook/NPG that the BCR might have a role in http://dx.doi.org/10.1016/j.immuni.2015.05.013 (2015) self-antigen presentation in the FURTHER READING Klein, L. et al. Positive and thymus. However, the authors negative selection of the T cell repertoire: what found that thymic B cell licensing thymocytes see (and don’t see). Nat. Rev. Immunol. 14, 377–391 (2014) did not depend on the BCR. In fact,

NATURE REVIEWS | IMMUNOLOGY VOLUME 15 | JULY 2015