Development of Peyer's patches and lymph nodes requires the interaction between CD4+ CD3- IL-7Ralpha+ lymphoid-tissue inducer (LTi) and VCAM-1+ organizer cells. Here we showed that by promoting their survival, enhanced expression of interleukin-7 (IL-7) in transgenic mice resulted in accumulation of LTi cells. With increased IL-7 availability, de novo formation of VCAM-1+ Peyer's patch anlagen occurred along the entire fetal gut resulting in a 5-fold increase in Peyer's patch numbers. IL-7 overexpression also led to formation of multiple organized ectopic lymph nodes and cecal patches. After immunization, ectopic lymph nodes developed normal T cell-dependent B cell responses and germinal centers. Mice overexpressing IL-7 but lacking either RORgamma, a factor required for LTi cell generation, or lymphotoxin alpha1beta2 had neither Peyer's patches nor ectopic lymph nodes. Therefore, by controlling LTi cell numbers, IL-7 can regulate the formation of both normal and ectopic lymphoid organs.
Significance
Group 3 innate lymphoid cells (ILC3s) play decisive roles in mammalian physiology including tissue repair, lymphoid tissue development, and immune regulation. So far, the functions of ILC3s in the adult immune system have been mainly linked to their capacity to release cytokines in response to microbial or inflammatory signals. The results presented here show that activated ILC3s can alter the outcome of adaptive immune responses by directly stimulating CD4
+
T cells. Indeed, IL-1β–activated ILC3s express costimulatory molecules and induce cognate CD4
+
T-cell responses. More importantly, antigen-driven T- and B-cell responses are impaired in vivo when this cellular interaction is disrupted. Overall, our data show that peripheral ILC3s play a yet unappreciated role in T-cell–mediated immunity.
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