A20 haploinsufficiency disturbs immune homeostasis and drives the transformation of lymphocytes with permissive antigen receptors

Abstract

Genetic <i>TNFAIP3</i> (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). In a cohort of 34 patients with HA20, we show that heterozygous <i>TNFAIP3</i> loss skews immune repertoires toward lymphocytes with classical self-reactive antigen receptors typically found in B and T cell lymphomas. This skewing was mediated by a feed-forward tumor necrosis factor (TNF)/A20/nuclear factor κB (NF-κB) loop that shaped pre-lymphoma transcriptome signatures in clonally expanded B (<i>CD81</i>, <i>BACH2</i>, and <i>NEAT1</i>) or T (<i>GATA3</i>, <i>TOX</i>, and <i>PDCD1</i>) cells. The skewing was reversed by anti-TNF treatment but could also progress to overt lymphoma. Analysis of conditional <i>TNFAIP3</i> knock-out mice reproduced the wiring of the TNF/A20/NF-κB signaling axis with permissive antigen receptors and suggested a distinct regulation in B and T cells. Together, patients with the genetic disorder HA20 provide an exceptional window into A20/TNF/NF-κB-mediated control of immune homeostasis and early steps of lymphomagenesis that remain clinically unrecognized.