4.7 Article

Failures in thymus medulla regeneration during immune recovery cause tolerance loss and prime recipients for auto-GVHD

Journal

JOURNAL OF EXPERIMENTAL MEDICINE
Volume 219, Issue 2, Pages -

Publisher

ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20211239

Keywords

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Funding

  1. Medical Research Council Programme Grant
  2. Imam Mohammad Ibn Saud Islamic University

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The thymus plays a crucial role in immune tolerance by synchronizing thymocyte development and selection. However, after bone marrow transplantation, a functional uncoupling of these processes can lead to post-transplant tolerance loss and autoimmunity. This is primarily caused by selective failures in thymus medulla regeneration, resulting in ineffective tolerance mechanisms and autoimmune reconstitution.
The thymus ensures immune tolerance by synchronizing thymocyte development and selection. Alawam et al. show that a functional uncoupling of these events occurs after bone marrow transplantation, which results in post-transplant tolerance loss and autoimmunity caused by selective failures in thymus medulla regeneration. Bone marrow transplantation (BMT) is a widely used therapy for blood cancers and primary immunodeficiency. Following transplant, the thymus plays a key role in immune reconstitution by generating a naive alpha beta T cell pool from transplant-derived progenitors. While donor-derived thymopoiesis during the early post-transplant period is well studied, the ability of the thymus to synchronize T cell development with essential tolerance mechanisms is poorly understood. Using a syngeneic mouse transplant model, we analyzed T cell recovery alongside the regeneration and function of intrathymic microenvironments. We report a specific and prolonged failure in the post-transplant recovery of medullary thymic epithelial cells (mTECs). This manifests as loss of medulla-dependent tolerance mechanisms, including failures in Foxp3(+) regulatory T cell development and formation of the intrathymic dendritic cell pool. In addition, defective negative selection enables escape of self-reactive conventional alpha beta T cells that promote autoimmunity. Collectively, we show that post-transplant T cell recovery involves an uncoupling of thymopoiesis from thymic tolerance, which results in autoimmune reconstitution caused by failures in thymic medulla regeneration.

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