Interleukin-21 (IL-21) Downregulates Dendritic Cell Cytokine Responses to Helicobacter pylori and Modulates T Lymphocyte IL-17A Expression in Peyer's Patches during Infection

Interleukin-21 (IL-21), a cytokine produced by many subsets of activated immune cells, is critical for driving inflammation in several models. Using Helicobacter pylori infection as a model for chronic mucosal infection, we previously published that IL-21 is required for the development of gastritis in response to infection. Concomitant with protection from chronic inflammation, H. pylori-infected IL-21(-/-) mice exhibited limited Th1 and Th17 responses in their gastric mucosa. Here we report that H. pylori-infected IL-21(-/-) mice express significantly higher levels of IL-17A than H. pylori-infected wild-type (WT) mice in the Peyer's patches and mesenteric lymph nodes. This led us to hypothesize that IL-21 may indirectly regulate H. pylori-specific T cell responses by controlling dendritic cell (DC) functions in mucosa-associated lymphoid tissue. It was found that IL-21 treatment reduced the ability of dendritic cells to produce proinflammatory cytokines in response to H. pylori. While H. pylori increased the expression of costimulatory proteins on DCs, IL-21 reduced the expression of CD40 in the presence of H. pylori. Also, Th17 recall responses were intact when DCs were used as antigen-presenting cells in the presence of IL-21, but IL-21 did impact the ability of DCs to induce antigen-specific proliferation. These data suggest that IL-21, while proinflammatory in most settings, downregulates the proinflammatory cytokine microenvironment through modulating the cytokine expression of DCs, indirectly modifying IL-17A expression. Understanding how these proinflammatory cytokines are regulated will advance our understanding of how and why H. pylori infection may be tolerated in some individuals while it causes gastritis, ulcers, or cancer in others.