TNFα-dependent development of lymphoid tissue in the absence of RORγt+ lymphoid tissue inducer cells

Lymphoid tissue often forms within sites of chronic inflammation. Here we report that expression of the proinflammatory cytokine tumor necrosis factor alpha (TNF alpha) drives development of lymphoid tissue in the intestine. Formation of this ectopic lymphoid tissue was not dependent on the presence of canonical RORgt(+) lymphoid tissue-inducer (LTi) cells, because animals expressing increased levels of TNFa but lacking RORgt(+) LTi cells (TNF/Rorc(gt)(-/-) mice) developed lymphoid tissue in inflamed areas. Unexpectedly, such animals developed several lymph nodes (LNs) that were structurally and functionally similar to those of wild-type animals. TNF alpha production by F4/80(+) myeloid cells present within the anlagen was important for the activation of stromal cells during the late stages of embryogenesis and for the activation of an organogenic program that allowed the development of LNs. Our results show that lymphoid tissue organogenesis can occur in the absence of LTi cells and suggest that interactions between TNF alpha-expressing myeloid cells and stromal cells have an important role in secondary lymphoid organ formation.