Deletion or Treg cell differentiation are alternative fates of autoreactive MHCII-restricted thymocytes. How these different modes of tolerance determine the size and composition of polyclonal cohorts of autoreactive T cells with shared specificity is poorly understood. We addressed how tolerance to a naturally expressed autoantigen of the central nervous system shapes the CD4 T cell repertoire. Specific cells in the tolerant peripheral repertoire either were Foxp3+ or displayed anergy hallmarks and, surprisingly, were at least as frequent as in the nontolerant repertoire. Despite this apparent lack of deletional tolerance, repertoire inventories uncovered that some T cell receptors (TCRs) were lost from the CD4 T cell pool, whereas others mediated Treg cell differentiation. The antigen responsiveness of these TCRs supported an affinity model of central tolerance. Importantly, the contribution of different diverter TCRs to the nascent thymic Treg cell population reflected their antigen reactivity rather than their frequency among precursors. This reveals a multilayered TCR hierarchy in CD4 T cell tolerance that separates deleted and diverted TCRs and assures that the Treg cell compartment is filled with cells of maximal permissive antigen reactivity.
|Original language||English (US)|
|Number of pages||7|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Sep 10 2019|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. This work was supported by the European Research Council (ERC-2016-ADG 742290–TOLERANCE FOOTPRINT to L.K.). M.H. and E.U. received support from the Deutsche Forschungsgemeinschaft (SFB 1054, projects A01 and IRTG). M.K.J. is supported by the US National Institutes of Health (P01 AI035296). D.H.B. received support from the Deutsche Forschungsgemeinschaft (SFB 1054, project B09). We thank L. Richter (FlowCyt Core Facility, BioMedical Center, Munich, Germany) for flow cytometry support.
- Clonal diversion
- MHC class II tetramer
- Regulatory T cell
- T cell tolerance