Alteration of interleukin 4 production results in the inhibition of T helper type 2 cell-dominated inflammatory bowel disease in T cell receptor α chain-deficient mice

Abstract

T cell receptor α chain-deficient (TCR-α(-/-) mice are known to spontaneously develop inflammatory bowel disease (IBD). The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4+TCR-ββ (CD4+ββ) T cells producing predominantly interleukin (IL)-4. To investigate the role of these Th2-type CD4+ββ T cells, we treated TCR-α(-/-) mice with anti-IL-4 monoclonal antibody (mAb). Approximately 60% of TCR-α(-/-) mice, including those treated with mock Ab and those left untreated, spontaneously developed IBD. However, anti-IL-4 mAb-treated mice exhibited no clinical or histological signs of IBD, and their levels of mucosal and systemic Ab responses were lower than those of mock Ab-treated mice. Although TCR-α(-/-) mice treated with either specific or mock Ab developed CD4+ββ T cells, only those treated with anti-IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon γ-specific expression. These findings suggest that IL-4-producing Th2-type CD4+ββ T cells play a major immunopathological role in the induction of IBD in TCR-α(-/-) mice, a role that anti-IL-4 mAb inhibits by causing Th2-type CD4+ββ T cells to shift to the Th1 type.