Cytotoxic T cells in H. pylori-related gastric autoimmunity and gastric lymphoma

Abstract

Helicobacter pylori infection is the major cause of gastroduodenal pathologies, but only a minority of infected patients develop gastric B-cell lymphoma, gastric autoimmunity, or other life threatening diseases, as gastric cancer or peptic ulcer. The type of host immune response against H. pylori, particularly the cytolytic effector functions of T cells, is crucial for the outcome of the infection. T cells are potentially able to kill a target via different mechanisms, such as perforins or Fas-Fas ligand interaction. In H. pylori-infected patients with gastric autoimmunity cytolytic T cells, that cross-recognize different epitopes of H. pylori proteins and H(+)K(+)-ATPase autoantigen, infiltrate the gastric mucosa and lead to gastric atrophy via long-lasting activation of Fas ligand-mediated appotosis and perforin-induced cytotoxicity. On the other hand, gastric T cells from MALT lymphoma exhibit defective perforin- and Fas-Fas ligand-mediated killing of B cells, with consequent abnormal help for B-cell proliferation, suggesting that deregulated and exhaustive H. pylori-induced T cell-dependent B-cell activation can support both the onset and the promotion of low-grade B-cell lymphoma.

Figure 1

Different cytotoxic functions of T cells in H. pylori-related gastric autoimmunity and gastric lymphoma. T cells are essential for defence against infection, but inappropriate Th responses can be harmful for the host. In susceptible individuals, H. pylori induces gastric autoimmunity via molecular mimicry by the expansion of H. pylori-specific T cells that cross-react with H⁺K⁺-ATPase epitopes. Cross-reactive T cells would result in destruction of gastric mucosa, by the long-lasting activation of both Fas-ligand (FasL)-induced apoptosis and perforin-mediated cytotoxicity. Conversely, in a minority of infected patients, gastric H. pylori-specific Th cells display deficient cytotoxic control (both perforin and Fas-Fas-ligand mediated) of B-cell growth. Such cytolytic defects, associated with the production of cytokines with B-cell growth factor activity and the chronic delivery of costimulatory signals by Th cells, together with chronic exposure to H. pylori antigens, would result in overgrowth of B cells, thus promoting the neoplastic B-cell transformation and the onset of gastric low-grade MALT B-cell lymphoma.