Defining the Helper T Cell Contribution to Helicobacter pylori Gastritis.

Abstract

Mouse models of H. pylori disease develop chronic gastritis due to an immune response dependent upon IFNg and CD4+ T cells, but several reports demonstrate that IL-17A, a cytokine associated with mucosal inflammatory responses, is elevated in gastric punch biopsies of infected human patients. To investigate the role of IL-17A in H. pylori gastritis I used C57Bl/6 (B6), IL-17A knockout (17AKO), IFNg knockout (IFNgKO), and CIITA transgenic (CIITA-Tg) mice in two distinct mouse models of disease. 17AKO mice developed less gastritis than B6 mice with greater bacterial colonization in simple infection experiments, but 17AKO and B6 T cells promoted equivalent gastritis and H. pylori colonization in adoptive transfer recipients, indicating that while IL-17A contributes to gastritis other inflammatory mechanisms may be at work in adoptive transfer. T cells from CIITA-Tg mice do not produce IL-17A but promote gastritis and cytokine expression similar to B6 T cells in recipient mice, but CIITA-Tg T cells recovered from transferred mice were hyporesponsive to H. pylori antigen stimulation, suggesting that gastritis progresses without antigen-specific Th1 or Th17 cells. Several innate inflammatory cytokines were induced by infection in all mice that developed disease, indicating that non-T cell effector populations contribute to disease development. To explore these cells I isolated leukocyte populations from gastric mucosa to analyze them via flow cytometry. Both the quantity of T cells and the ratio of regulatory to effector T cells in transfer experiments affected the quantities of lymphocytes, granulocytes and myeloid cells in situ as well as influencing gastritis severity. Transfer of IFNgKO and 17AKO T cells significantly altered the populations of leukocytes but not disease severity, suggesting that gastritis in adoptive transfer requires T cells to develop disease without needing specific T cell cytokines. Together, these observations indicate that IL-17A and IFNg both contribute to gastritis development in H. pylori infected mice and may be necessary for early promotion of gastritis, but disease may continue in an antigen-independent fashion late in infection. We have also clearly underestimated the importance of innate effector cells in mouse models of H. pylori gastritis, as these cells actively participate to promote disease development.