Helicobacter pylori-Induced Th17 Responses Modulate Th1 Cell Responses, Benefit Bacterial Growth, and Contribute to Pathology in Mice

Abstract

CD4+ T cell responses are critical for the pathogenesis of Helicobacter pylori infection. The present study evaluated the role of the Th17 subset in H. pylori infection. H. pylori infection induced significant expression of IL-17 and IFN-g in mouse gastric tissue. IL-23 and IL-12 were increased in the gastric tissue and in H. pylori-stimulated macrophages. Cell responses were examined by intracellular staining for IFN-g, IL-4, and IL-17. Mice infected with H. pylori developed a mixed Th17/Th1 response; Th17 responses preceded Th1 responses. Treatment of mice with an anti-IL-17 Ab but not a control Ab significantly reduced the H. pylori burden and inflammation in the stomach. H. pylori colonization and gastric inflammation were also lower in IL-17 2/2 mice. Furthermore, administration of recombinant adenovirus encoding mouse IL-17 increased both H. pylori load and inflammation. Further analysis showed that the Th1 cell responses to H. pylori were downregulated when IL-17 is deficient. These results together suggest that H. pylori infection induces a mixed Th17/Th1 cell response and the Th17/IL-17 pathway modulates Th1 cell responses and contributes to pathology. The Journal of Immunology, 2010, 184: 5121-5129. H elicobacter pylori is a Gram-negative, microaerophilic bacterium that resides extracellularly in the gastric mucosa and infects .50% of the population worldwide. H. pyloriinduced chronic inflammation is the cause of gastritis and peptic ulcers and a risk factor for gastric cancer (1, 2). H. pylori infection causes severe local inflammation in the gastric mucosa. CD3 + CD4 + T cells are increased in infected gastric lamina propria and play important roles in the pathogenesis of persistent H. pylori infection (3). Traditionally, CD4 + T cells are classified into two main classes: Th1 and Th2, on the basis of their cytokine secretion and immune regulatory function. Th1 cells secrete IFN-g, IL-2, and IL-12 and regulate cellular immunity, whereas Th2 cells produce IL-4, IL-5, and IL-13 and mediate humoral responses. To date, studies of immune responses to H. pylori have largely focused on Th1 and Th2 cells, and it is generally accepted that H. pylori infection results in a Th1-dominant response and that gastric inflammation largely depends on Th1 cell responses (3-6); however, IFN-g secretion alone is insufficient to induce gastritis (3). Thus, the detailed mechanism of pathogenesis is not clear. A novel subset of effector T cells, identified by secretion of IL-17, has been defined as Th17 cells. Th17 cells are distinct from Th1 and Th2 cells in their differentiation and function (7,8). TGF-b and IL-6 from activated macrophages/dendritic cells are required for Th17 cell differentiation in murine systems (9), whereas IL-12 and IFN-g promote Th1 cell development and IL-4 primes Th2 cell differentiation. The expansion and survival of Th17 cells are promoted by IL-23 (9), a heterodimeric cytokine composed of a unique p19 subunit and a p40 subunit shared with IL-12 (10). The identification of Th17 cells necessit...

Bacterial chemotaxis modulates host cell apoptosis to establish a T-helper cell, type 17 (Th17)-dominant immune response in Helicobacter pylori infection

“…3C). This finding is consistent with previous evidence showing IL-17 expression in H. pylori-infected gastric tissue (9,12,17). Furthermore, studies have shown that depletion of IL-17 or the use of IL-17 −/− mice lowers both H. pylori colonization levels and inflammation grade (12).…”

“…However, the roles of the Th17 and T-reg cell populations during H. pylori infections have been debated recently. The Th17 cell is involved in promoting chronic inflammation (11,12); the Treg cell, in contrast, regulates host immune responses. Th17 and Treg cells are developmentally related and exist in a delicate balance (13) that can dictate the outcome of a bacterial infection (14).…”

Cytokine BAFF Released byHelicobacter pylori–Infected Macrophages Triggers the Th17 Response in Human Chronic Gastritis

“…Many data support the idea that the Th17 response favors the bacterial growth in mice and contributes to the inflammation both in mice and in humans (3)(4)(5), although its role is probably not essential because IFN-g has the largest effect (2). Along with this evidence, other data suggest that this response may exert a regulatory effect rather than a proinflammatory one (6).…”

“…The infiltration of Th17 cells in the gastric mucosa of H. pyloriinfected patients is well established (3,21). To confirm this evidence, we evaluated the expression of IL-17, in terms of both mRNA and protein, in the mucosa of H. pylori-infected patients with nonatrophic chronic gastritis, a condition that represents a risk for the development of more severe gastric diseases (22).…”

“…It has been proposed that Th17 cells precede and may regulate the Th1 response and contribute to the pathology in mice (3), but the real contribution of the IL-17 activity in H. pylori-induced diseases remains a controversial issue. Many data support the idea that the Th17 response favors the bacterial growth in mice and contributes to the inflammation both in mice and in humans (3)(4)(5), although its role is probably not essential because IFN-g has the largest effect (2).…”