The role of recirculating thymic T regulatory cells in regulation of de novo T reg development and central tolerance.

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Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B998
Abstract ID: 5191

Presenting Author:
Sookyong Joo , Graduate Research Assistant at Univ. of Minnesota Med. Sch.

Abstract:

AIRE+ medullary thymic epithelial cells (mTECS) play a key role in establishing immune tolerance. These cells peak 2-3 weeks after birth and then steadily decline as mice get older. The mechanism by which AIRE+ mTECs decline remains unclear. We observed that a subset of recirculating thymic T regulatory cells (RT-Tregs) accumulates in the thymus at the same time that AIRE+mTECs decline. Using scRNA-Seq we found that RT-Tregs are quite diverse and may have cytotoxic potential. We propose that RT-Tregs play an essential role in balancing the stringency of T cell selection in the thymus by regulating mTEC abundance. To test this hypothesis we injected diphtheria toxin (DT) into the thymus of FOXP3-DTR mice, which selectively deplete RT-Tregs, but not de novo generated thymic Tregs or peripheral Tregs. This treatment led to a substantial increase in the number of AIRE+ mTECs. Using previously published datasets, we observed that the TCR diversity of conventional T cells (Tconv) in lymphoid organs of AIRE^-/- mice was significantly increased relative to that of WT mice. We are currently testing whether depletion of RT-Tregs results in the opposite phenotype - a less diverse Tconv repertoire. We propose that early in life AIRE+ mTECs promote self-tolerance. RT-Tregs then act in a feedback loop to signal that peripheral tolerance has been established and eliminate AIRE+ mTECs resulting in a more diverse TCR repertoire that may be more self-reactive but also more pathogen-reactive.