LUBAC-mediated signals in thymic epithelial cells prevent early thymic atrophy and immunodeficiency

Abstract

Abstract Thymic epithelial cells (TECs) govern the differentiation of haematopoietic precursors into functional T cells. Defects in this process can lead to immunodeficiency and autoimmune disease. Distinct signals from members of the TNF receptor superfamily have key roles in TEC proliferation and differentiation, yet it remains unclear how these stimuli are integrated to support thymus function. We find that components of the linear ubiquitin chain assembly complex (LUBAC) that act downstream of TNFR signaling to regulate NFkB activity are essential for TEC homeostasis and thymic function. TEC-specific loss of LUBAC proteins, HOIL-1 or HOIP, induced early thymic atrophy shortly after birth, with severe loss of tissue in 2-month-old adult mice attended by gross defects in peripheral T cell populations. The requirement for HOIL-1 or HOIP extended to all major TEC subsets, including those expressing the autoimmune regulator, AIRE. In contrast, loss of a third LUBAC component in SHARPIN-deficient mice (Shcpdm/cpdm) had a milder impact, reducing TECs in the thymic medulla that require CD40 signals for their maintenance. Ablation of TNF or Caspase 8 and RIPK3 in Shcpdm/cpdm mice failed to rescue these defects, indicating that CD40/SHARPIN signals are not required to prevent TNF-induced cell death. These differential roles for LUBAC components in TEC correlate with their function in linear ubiquitylation and reveal a critical signaling hub in the maintenance of the thymic microenvironment