Interleukin-22 Drives Endogenous Thymic Regeneration in Mice

Abstract

Endogenous thymic regeneration is a crucial function that allows for renewal of immune competence after stress, infection or immunodepletion. The mechanisms governing this regeneration, however, remain poorly understood. Here we detail a framework of thymic regeneration centred on IL-22 and triggered by depletion of CD4+CD8+ double positive (DP) thymocytes. Intrathymic levels of IL-22 were increased following thymic insult, and thymic recovery was impaired in IL-22-deficient mice. IL-22, which signalled through thymic epithelial cells (TECs) and promoted their proliferation and survival, was upregulated by radio-resistant RORγ(t)+CCR6+NKp46− lymphoid tissue-inducer cells (LTi) after thymic injury in an IL-23 dependent manner. Importantly, administration of IL-22 enhanced thymic recovery following total body irradiation (TBI). These studies reveal mechanisms of endogenous thymic repair and offer innovative regenerative strategies for improving immune competence.

Innate Lymphoid Cells in Graft-Versus-Host Disease

“…The significance of ILC3‐derived IL‐22 after immunodepletion was also shown in the enhanced regeneration of thymic epithelial cells and in the reconstitution of thymic T cell compartments 36. The identified cellular cascade after thymic injury consisted of upregulation of radio‐resistant CD103 + DCs providing IL‐23, which in turn stimulated IL‐22 release from RORγt + CCR6 + NKp46 − LTi cells in the thymus.…”

Acute Thymic Involution and Mechanisms for Recovery

“…Recombinant IL-7 therapy enhances the total numbers of T stem cells and restores the diversity of the T cell repertoire following cytotoxic chemotherapy in human beings (Zhang et al 2015). Moreover, administration of IL-22 can accelerate the endogenous thymic repair following sub-lethal total body irradiation in mice (Dudakov et al 2012).…”

Interleukin‐21 administration to aged mice rejuvenates their peripheral T‐cell pool by triggering de novo thymopoiesis

“…Unfortunately, however, BM‐derived progenitor numbers decline markedly with age due to increased apoptosis rates as well as reduced proliferative capacities (Min et al ., 2004). This in turn negatively impacts the delicate thymic stromal compartment, which is dependent on cross talk interactions with thymic progenitors for its sustained survival and morphogenesis (Shores et al ., 1991; Hollander et al ., 1995; van Ewijk et al ., 2000; Dudakov et al ., 2012). In this regard, two major points can be concluded based on observations made in rIL‐21‐treated aged mice.…”