Knockdown of twist1 increases the production of TNF (red) in the arthritic joints of mice.
Th1 cells activated by self-antigens can cause chronic inflammation, as seen in autoimmune diseases such as diabetes and rheumatoid arthritis. Niesner et al. were searching for genes that are highly expressed in such chronically activated Th1 cells in mice and discovered a transcriptional repressor called twist1. Now, the authors show that repeatedly activated Th1 cells avoid turning deadly by turning on twist1, which then inhibits NF-κB–dependent cytokine production.
Absent in naive mouse T cells, twist1 was switched on when these cells were stimulated with antigen in the presence of the Th1 polarizing cytokine IL-12 but not the Th2 cytokine IL-4. IL-12 activates the transcriptional activator STAT4, which then bound to and activated the twist1 promoter. Subsequent antigen stimulation increased twist1 expression in the Th1 cells, dampening their inflammatory cytokine production. The delayed induction of twist1 probably gives Th1 cells a chance to initiate inflammation before they are shut down.
An infusion of twist1-deficient Th1 cells worsened arthritis in mice, whereas a shot of Th1 cells overexpressing twist1 ameliorated disease. Before this finding can be clinically exploited, a twist in the human twist1 story needs to be sorted out: Th1 cells found in the diseased tissues of patients suffering from arthritis or chronic gut inflammation had plenty of twist1. Whether human twist1 also acts as a brake and, if so, how these disease-associated Th1 cells bypass it remains to be seen.
