Functional adaptation of intrathymically differentiating B cells for central T cell tolerance
Final Report Abstract
The thymus harbors a variety of antigen presenting cell (APC) types that co-operatively orchestrate the generation of a functional and self-tolerant T cell repertoire. Besides cortical thymic epithelial cells (cTECs), medullary thymic epithelial cells (mTECs) and ‘classical’ dendritic cells (cDCs), all comparably well studied cell types, the thymus also harbors B cells. In the present project, we aimed to investigate whether thymic B cells display unique tolerogenic features that distinguish them from peripheral B cells. We identified expression of the autoimmune regulator gene (Aire) as a surprising characteristic of thymic B cells not shared by B cells in spleen and bone marrow. In further distinction from B cells in other organs, thymic B cells are homogenously MHCIIhigh and CD80+, thus displaying a potent APC surface-phenotype. A comparison of gene expression profiles of thymic B cells from WT and Aire−/− mice reveals an Aire-dependent transcriptome in thymic B cells that includes ‘peripheral antigens’. We considered that Aire+MHCIIhighCD80+ thymic B cells may represent an intrathymically differentiating specialized ‘tolerogenic B cell lineage’. However, this does not appear to be the case. Instead, we found that immigration of peripheral ‘mainstream’ B cells into the thymus induces phenotypic changes that recapitulate the distinct hallmarks of steady state thymic B cells. We refer to this microenvironmental programming as ‘thymic B cell licensing’. We showed that thymic B cells (but not peripheral B cells) directly present an endogenous model-antigen whose induction reflects and depends upon intrathymic B cell licensing and demonstrate that a model self–antigen that is exclusively expressed by immigrating peripheral B cells in a licensing-dependent manner mediates central tolerance. In sum, our findings identify intrathymic B cell licensing as a hitherto unrecognized functional adaptation of a thymic APC subset. These observation reveal a novel layer of quality control during central T cell tolerance induction.
Publications
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(2015) Thymic B cells and Central T Cell Tolerance. Frontiers in Immunology 6:376
Yamano T., Steinert M. and Klein L.
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(2015) Thymic B cells are licensed to present self antigens for central T cell tolerance induction. Immunity, 42(6): 1048-1061
Yamano T., Nedjic J., Hinterberger M., Steinert M., Koser S., Pinto S., Gerdes N., Lutgens E., Ishimaru N., Busslinger M., Brors B., Kyewski B. and Klein L.
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(2018) B cells latently infected with murine gammeherpesvirus 68 (MHV-68) are present in the mouse thymus – a step towards immune evasion? European Journal of Immunology
Yamano T., Steinert M., Steer B., Klein L., Hammerschmidt W. and Adler H.
