A critical epithelial survival axis regulated by MCL-1 maintains thymic function

Abstract

Abstract T cell differentiation is governed by interactions with thymic epithelial cells (TECs) and defects in this process undermine immune function. Age-related thymic involution is recognised as a potentially fatal brake on immune recovery following haematopoietic stem/progenitor cell transplantation and cancer treatments. To uncover new strategies to restore thymic function, we determined the molecular mechanisms that control life and death decisions in TEC. We recently published that while TEC-specific deletion of pro-survival proteins BCL-2 and BCL-XL did not cause gross abnormalities, MCL-1 deficiency impacted on TEC as early as E15.5, resulting in early thymic atrophy, T cell lymphopenia, with near complete loss of thymic tissue by 2 months of age. MCL-1 was continually required for the survival of medullary TEC, including autoimmune regulator (AIRE) expressing TECs and the maintenance of overall thymic architecture. A screen of TEC trophic factors in organ cultures showed that epidermal growth factor upregulated MCL-1 via the MAPK/ERK kinase activity, providing a molecular mechanism for the support of TEC survival. However, these findings do not imply that the intrinsic pathway of apoptosis necessarily controls TEC death during homeostasis. Therefore, we removed essential effectors of this pathway, BAX and BAK, specifically in TECs and found that there was a specific increase in a medullary TEC subset leading to an overall increase in TEC numbers both in young and old mice. This signalling axis governing TEC survival, death and thymic function represent a compelling strategy for protecting the thymus during blood cancer treatment to prevent immunodeficiency, without counterproductive survival of haematopoietic lineages.