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
- (2015) Thymic B cells and Central T Cell Tolerance. Frontiers in Immunology 6:376
Yamano T., Steinert M. and Klein L.
(See online at https://doi.org/10.3389/fimmu.2015.00376) - (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.
(See online at https://doi.org/10.1016/j.immuni.2015.05.013) - (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.
(See online at https://doi.org/10.1002/eji.201847886)
