Autoregulation of Th1-mediated infl ammation by twist1

The basic helix-loop-helix transcriptional repressor twist1 , as an antagonist of nuclear factor B (NF- B) - dependent cytokine expression, is involved in the regulation of infl am- mation-induced immunopathology. We show that twist1 is expressed by activated T helper (Th) 1 effector memory (EM) cells. Induction of twist1 in Th cells depended on NF- B, nuclear factor of activated T cells (NFAT), and interleukin (IL)-12 signaling via signal transducer and activator of transcription (STAT) 4. Expression of twist1 was transient after T cell receptor engagement, and increased upon repeated stimulation of Th1 cells. Imprint- ing for enhanced twist1 expression was characteristic of repeatedly restimulated EM Th cells, and thus of the pathogenic memory Th cells characteristic of chronic infl ammation. Th lymphocytes from the infl amed joint or gut tissue of patients with rheumatic diseases, Crohn ' s disease or ulcerative colitis expressed high levels of twist1 . Expression of twist1 in Th1 lymphocytes limited the expression of the cytokines interferon- , IL-2, and tumor necrosis factor- , and ameliorated Th1-mediated immunopathology in delayed-type hyper- sensitivity and antigen-induced arthritis.