Abstract

Both physiological and psychological stress cause thymic atrophy via glucocorticoïd (GC)-dependent apoptosis of double-positive (DP) thymocytes. Given the pervasiveness of stress, GC-induced thymic atrophy is arguably the most common type of acquired immunodeficiency. We recently reported that interleukin-21 (IL-21) has a unique ability to expand the small subset of DP thymocytes (CD69+) which are ongoing positive selection, and that administration of IL-21 increases thymic output in aged mice. The goal of this study was to evaluate whether IL-21 could mitigate GC-induced thymic atrophy. In contrast to double-negative (DN) and single-positive (SP) thymocytes, most DP thymocytes (CD69−) do not constitutively express the IL-21 receptor (IL-21R). Accordingly, CD69− DP thymocytes from PBS-treated mice were unresponsive to IL-21 administration. However, following GC injection, surviving CD69− DP thymocytes up-regulated IL-21R and responded to IL-21 treatment as evidenced by enhancement of Bcl6 expression and phosphorylation of STAT1, STAT3 and STAT5. Consequently, IL-21 administration to GC-treated mice accelerated thymic recovery by expanding considerably DP thymocytes and, to a lesser extent, DN thymocytes. However, IL-21-induced expansion of DN/DP thymocytes did not alter the diversity of the intrathymic or peripheral T-cell receptor (TCR) repertoire. We conclude that IL-21 dramatically accelerates recovery from GC-induced thymic atrophy.

Highlights

  • The thymus is critical for sustained T-cell development in vertebrates [1,2]

  • Analyses conducted on fractionated DN thymocytes showed similar IL-21 receptor (IL-21R) expression on early thymic progenitors (ETPs - cKit+CD8b-Lin-TCRb-CD252), DN2 as well as DN3 thymocytes (CD4282Lin-CD25+CD442) (Fig. 1C)

  • While IL-21R was undetectable on the whole DP population from PBS-injected mice, it was clearly upregulated on DP thymocytes from DEX

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Summary

Introduction

The thymus is critical for sustained T-cell development in vertebrates [1,2]. The thymus undergoes early agerelated involution characterized by a decline in thymic cellularity and output [3,4]. The stress response is characterized by the triad of enlarged adrenal glands, gastric erosions and thymic atrophy [6]. GCs produced by hyperactive adrenal glands trigger apoptosis of DP thymocytes in an Apaf-1- and caspase-9-dependent manner [4,7]. Since acute and chronic GC-induced thymic atrophy are associated with increased frequency and severity of infectious diseases [15,16,17], exposure to endogenous or exogenous GCs is arguably the most common type of acquired immunodeficiency in human

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