Influenza A virus-induced thymus atrophy differentially affects dynamics of conventional and regulatory T-cell development in mice.

Yassin Elfaki,Immo Prinz,Stefan Floess,Jochen Huehn,Dunja Bruder,Michael Meyer‐Hermann,Christine S. Falk,Philippe A. Robert,Christoph Binz

doi:10.1002/eji.202048981

Abstract

Foxp3+ Treg cells, which are crucial for maintenance of self-tolerance, mainly develop within the thymus, where they arise from CD25+ Foxp3- or CD25- Foxp3+ Treg cell precursors. Although it is known that infections can cause transient thymic involution, the impact of infection-induced thymus atrophy on thymic Treg (tTreg) cell development is unknown. Here, we infected mice with influenzaA virus (IAV) and studied thymocyte population dynamics post infection. IAV infection caused a massive, but transient thymic involution, dominated by a loss of CD4+ CD8+ double-positive (DP) thymocytes, which was accompanied by a significant increase in the frequency of CD25+ Foxp3+ tTreg cells. Differential apoptosis susceptibility could be experimentally excluded as a reason for the relative tTreg cell increase, and mathematical modeling suggested that enhanced tTreg cell generation cannot explain the increased frequency of tTreg cells. Yet, an increased death of DP thymocytes and augmented exit of single-positive (SP) thymocytes was suggested to be causative. Interestingly, IAV-induced thymus atrophy resulted in a significantly reduced T-cell receptor (TCR) repertoire diversity of newly produced tTreg cells. Taken together, IAV-induced thymus atrophy is substantially altering the dynamics of major thymocyte populations, finally resulting in a relative increase of tTreg cells with an altered TCR repertoire.

Highlights

CD4+ Treg cells, which express the lineage-specification factor forkhead box P3 (Foxp3), constitute a subset of CD4+ T cells that is crucial for the maintenance of immune homeostasis and selftolerance [1]
Frequency of thymus-derived Treg (tTreg) cells and their CD25–Foxp3+ precursors increases upon Influenza A virus (IAV)-induced thymus atrophy
In order to study the impact of IAV-induced thymus atrophy on tTreg cell development, we performed a kinetic analysis by infecting adult Foxp3hCD2xRag1GFP doublereporter mice with a mouse-adapted strain of IAV (PR8M) and analyzing their thymi at different time points postinfection

Summary

Introduction

CD4+ Treg cells, which express the lineage-specification factor forkhead box P3 (Foxp3), constitute a subset of CD4+ T cells that is crucial for the maintenance of immune homeostasis and selftolerance [1]. Infection-induced thymus atrophy is thought to be beneficial, since a temporary cessation in T-cell production might limit the effect of dominant tolerance on the course of the infection [13]. Interferon-α has been reported as a critical molecular mediator of infection-induced thymus atrophy, and sensitivity of the thymic epithelium is controlled by a sophisticated microRNA network [14, 15]. It is important to note that thymic involution during infection is a very rapid yet transient phenomenon, with recovery within 1 to 2 weeks [14]. Despite this ample knowledge it has not yet been elucidated whether infection-induced thymus atrophy leads to changes in tTreg cell development

Methods

Results

Conclusion