Critical role of SP thymocyte motility in regulation of thymic output in neonatal Aire-/- mice.

Rong Jin,Jia Wu,Yu Zhang,Qing Ge,Yuqing Wang,Abudureyimujiang Aili,Xiuyuan Sun

doi:10.18632/oncotarget.13909

Abstract

Autoimmune regulator (Aire) is essential in the perinatal period to prevent the multiorgan autoimmunity. Here we show that Aire-regulated single positive thymocyte trafficking in neonatal period is critical for thymic egress. Reduced thymic emigration was found in Aire−/− mice during neonatal period, leading to enhanced homeostatic expansion of peripheral T cells as early as 2 weeks of age. In neonatal Aire−/− mice, thymic expression of CCR7 ligands were dramatically reduced, resulting in decreased thymocyte motility and thymocyte emigration. This reduction of thymic egress in Aire−/− mice was alleviated beyond 3 weeks of age by an early upregulation of S1P1 signaling. As the numbers and quality of thymic emigrants are essential for the establishment and maintenance of peripheral tolerance, the reduced thymic emigration during neonatal period may deteriorate autoimmunity caused by the emigration of autoreactive T cells.

Highlights

The autoimmune regulator (Aire) is found as a transcription factor that plays an essential role in the regulation of central tolerance and medullary thymic epithelial cells (mTECs) differentiation [1]
To investigate thymic egress in Aire-/- mice, we used two approaches to measure the numbers of recent thymic emigrants (RTEs)
The disparities in the cell number and percentage of CD8+ RTEs between neonatal Aire-/- and wild type (WT) mice were smaller than CD4+ RTEs (Figure 1B)

Summary

Introduction

The autoimmune regulator (Aire) is found as a transcription factor that plays an essential role in the regulation of central tolerance and mTEC differentiation [1]. Aire deficiency leads to failure in negative selection of single positive (SP) thymocytes and the development of a variety of autoantibodies and lymphocytic infiltration in multiple tissues both in human and in mice [2,3]. Aire-/- thymus showed a delay in CD4+ T cell emigration as early as 5-day after birth [6]. As Diane Mathis’s group showed that Aire was essential in perinatal period to prevent the multiorgan autoimmunity [8], the defect in T cell egress during this period implicates that SP thymocyte emigration may have a role in preventing autoimmunity

Methods

Results

Conclusion