Helicobacter pylori-Specific CD4⁺T Cells Home to and Accumulate in the HumanHelicobacter pylori-Infected Gastric Mucosa

Abstract

Helicobacter pylori infects the stomach and duodenal mucosa. T cells are important components of the H. pylori-induced immune response, but little is currently known about how these cells are recruited to the infected mucosa. Here, we have characterized stomach and duodenal T cells isolated from H. pylori-infected and noninfected subjects with regard to subtype, expression of homing and chemokine receptors, and in vitro reactivity to H. pylori antigens. Higher numbers of CD4؉ but similar numbers of CD8 ؉ lamina propria T cells were isolated from stomach biopsies from H. pylori-positive compared to H. pylori-negative individuals. CD4 Helicobacter pylori colonizes the mucus layer and the epithelium in the stomach as well as areas of gastric metaplasia in the duodenum. Most infected individuals remain asymptomatic, but 10 to 15% of those infected develop peptic ulcers, and 1 to 2% develop gastric cancer (13). H. pylori infection induces gastritis with infiltration of neutrophils, macrophages, dendritic cells, as well as B and T cells into the stomach lamina propria (13, 38). A majority of H. pylori-infected individuals also develop duodenitis (16, 44), but less is known about the duodenal immune responses to the infection.T cells seem to play an important role in the immunity against H. pylori. The mucosal inflammation induced by H. pylori is T-cell dependent, as H. pylori infection does not induce gastritis in T-cell-deficient mice, unless T cells are transferred to the mice (10). However, the natural T-cell responses to H. pylori are not protective, as the infection normally remains for life. Recent studies indicate that regulatory T cells suppress the T-cell responses to H. pylori infection, thereby contributing to the persistent bacterial colonization (25,26,36). However, vaccination can induce partial protection against Helicobacter infections in mice, and CD4 ϩ T cells have been shown to be important for this protection. Thus, protection cannot be achieved in mice lacking CD4 ϩ T cells, whereas protection can be induced in the absence of B cells or CD8 ϩ T cells (12,31,42). The natural T-cell response to H. pylori is of the Th1 type (23), and this type of response also seems to be involved in vaccine-induced protection against the infection (3).To achieve protection after vaccination, T cells have to be recruited to the stomach mucosa. Thus, Michetti et al. demonstrated that immunization-induced protection against H. felis infection is abolished by administration of antibodies that block the interaction between the ␣ 4 ␤ 7 integrin expressed by gut-homing lymphocytes and the mucosal addressin cellular adhesion molecule 1 (MAdCAM-1) expressed on endothelial cells in intestinal as well as gastric mucosa (28). Less is known about how T cells are recruited to the gastrointestinal mucosa during natural H. pylori infection. However, indirect evidence suggests that the homing receptors ␣ 4 ␤ 7 and L-selectin both mediate homing of H. pylori-specific T cells to H. pyloriinfected human mucosa. Thus, circulating T cell...

Helicobacter pylori invades the gastric mucosa and translocates to the gastric lymph nodes

“…All specimens were counterstained with Mayer's hematoxylin. The IHC results were considered to be positive when 10 Finally, sections were coverslipped with fluorescence mounting medium (DAKO). Stained sections were observed and photographed using a microscope BZ-9000 (Keyence, Osaka, Japan).…”

“…7 The development of H. pylori-induced chronic gastritis depends predominantly on the Th1-type T-cell response. 8,9 The accumulation of H. pylori-specific CD4 þ T cells in the H. pylori-infected human gastric mucosa 10 suggests that CD4 þ T-cell-mediated Th1 immune responses have a critical role in the development of H. pylori-induced gastritis. Where CD4 þ T cells are primed by H. pylori antigens and how the H. pylori-induced chronic inflammation is maintained by T cells, however, are unclear because H. pylori appears not to be invasive and rarely infiltrates the gastric mucosa.…”

Effects of a Th1- versus a Th2-biased immune response in protection against Helicobacter pylori challenge in mice

“…pylori infection is atypical in that it causes a cellular infiltration of neutrophils and CD4 positive lymphocytes, as well as secretion of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). This response is characteristic of a T helper type 1 (Th1) immune response, which is typically associated with intracellular pathogens [10][11][12]. This observation prompted early vaccine research to focus on the induction of T helper type 2 (Th2) immunity, since it was suspected that Th1 immunity prevented clearance from the host.…”

Helicobacter pylori infection reduces disease severity in an experimental model of multiple sclerosis

“…In patients, H. pylori infection is associated with alterations in the profile of homing receptors expressed by peripheral blood T cells, directing their migration toward the inflamed gastric mucosa (Lundgren et al, 2005). We previously showed that H. pylori infection results in increased proportions of human peripheral blood Tregs that express the chemokine receptor CCR6 .…”

“…In the vast majority of cases, however, colonization leads to asymptomatic chronic gastritis, with increased infiltration of neutrophils, dendritic cells (DCs), macrophages, natural killer (NK) cells, and lymphocytes into the gastric mucosa (reviewed in Robinson and Atherton, 2010;Koch et al, 2013). There is increased abundance of pro-inflammatory T-helper 1 (Th1) and Th17 subsets, as well as anti-inflammatory regulatory T cells (Tregs) (Lundgren et al, 2005;Robinson et al, 2008;Serrano et al, 2013). Infected individuals without gastroduodenal disease tend to have a more robust Treg response, which may also provide protection against extra-gastric conditions such as asthma, allergy, and inflammatory bowel disease (Kao et al, 2010;Arnold et al, 2011Arnold et al, , 2012Wang et al, 2013;Amberbir et al, 2014).…”