Autoimmune-Mediated Thymic Atrophy Is Accelerated but Reversible in RelB-Deficient Mice

Abstract

Polymorphisms impacting thymic function may decrease peripheral tolerance and hasten autoimmune disease. The NF-κB transcription factor subunit, RelB, is essential for the development and differentiation of medullary thymic epithelial cells (mTECs): RelB-deficient mice have reduced thymic cellularity and markedly fewer mTECs, lacking AIRE. The precise mechanism of this mTEC reduction in the absence of RelB is unclear. To address this, we studied mTECs and dendritic cells (DCs), which critically regulate negative selection, and thymic regulatory T-cells (tTreg) in RelB−/− mice, which have spontaneous multiorgan autoimmune disease. RelB−/− thymi were organized, with medullary structures containing AIRE− mTECs, DCs, and CD4+ thymocytes, but fewer tTreg. Granulocytes infiltrated the RelB−/− thymic cortex, capsule, and medulla, producing inflammatory thymic medullary atrophy, which could be treated by granulocyte depletion or RelB+ DC immunotherapy, with concomitant recovery of mTEC and tTreg numbers. These data indicate that central tolerance defects may be accelerated by autoimmune thymic inflammation where impaired RelB signaling impairs the medullary niche, and may be reversible by therapies enhancing peripheral Treg or suppressing inflammation.

The thymoproteasome hardwires the TCR repertoire of CD8+ T cells in the cortex independent of negative selection

“…4, D and E). In accordance with and in response to the multiorgan inflammation (Weih et al, 1995;O'Sullivan et al, 2018), thymic atrophy as measured by the reduced number of total thymocytes was detected in relB-deficient mice mildly at 1 wk old and moderately at 2 wk old (Fig. 4 F and Fig.…”

Transposable elements regulate thymus development and function

“…PAX1 is essential for the development of TEC progenitors (50), and RELB is for the development and differentiation of mTECs (80). RelB-deficient mice have reduced thymic cellularity, markedly fewer mTECs, lack Aire expression, and suffer from autoimmunity (49, 81). Under the influence of Aire, Fezf2, and Chd4, mTECs collectively express almost the entire exome (63, 64).…”

Primary and secondary defects of the thymus

“…This is, for example, the case in mice deficient in RelB, an NFKB transcription factor subunit, RANK, which selectively stimulates the noncanonical NFKB, and NFKB 1 and 2 deficient mice and humans. 109,110 In another mouse model, thymic central tolerance was disrupted by murine roseolavirus infection, which induces autoimmune gastritis. 111 Thymic atrophy can also be secondary to acute GVHD, with the process of negative selection notably impaired, which may cause chronic autoimmune manifestations affecting the skin or the salivary gland, for example.…”

“…Multiorgan autoimmune disease with reduced lifespan occurs also if NFKB signaling is impaired, which is essential for the development and differentiation of mTECs, causing thymic medullary atrophy. This is, for example, the case in mice deficient in RelB, an NFKB transcription factor subunit, RANK, which selectively stimulates the noncanonical NFKB, and NFKB 1 and 2 deficient mice and humans 109,110 . In another mouse model, thymic central tolerance was disrupted by murine roseolavirus infection, which induces autoimmune gastritis 111 .…”