Adoptive Transfer of CD4⁺T Cells Specific for Subunit A ofHelicobacter pyloriUrease ReducesH. pyloriStomach Colonization in Mice in the Absence of Interleukin-4 (IL-4)/IL-13 Receptor Signaling

Abstract

Protection in the murine model of Helicobacter pylori infection may be mediated by CD4؉ T cells, but the mechanism remains unclear. To better understand how protection occurs in this model, we generated and characterized H. pylori urease-specific CD4 ؉ T cells from BALB/c mice immunized with Salmonella enterica serovar Typhimurium expressing H. pylori urease (subunits A and B). The CD4 ؉ T cells were found to be specific for subunit A (UreA). Upon antigen-specific stimulation, expression of interleukin 4 (IL-4), IL-10, gamma interferon (IFN-␥), and tumor necrosis factor alpha was induced. Immunocytochemical analysis showed that the majority of cells produced IFN-␥ and IL-10. Adoptive transfer of the UreA-specific CD4 ؉ T cells into naive syngeneic recipients led to a threefold reduction in the number of bacteria in the recipient group when compared to that in the nonrecipient group. Stomach colonization was also reduced significantly after transfer of these cells into patently infected mice. Adoptive transfer of UreA-specific CD4 ؉ T cells into IL-4 receptor ␣ chain-deficient BALB/c mice indicated that IL-4 and IL-13 were not critical in the control of bacterial load. In addition, synthetic peptides were used to identify three functional T-cell epitopes present in subunit A which were recognized by the UreA-specific T cells. Analysis of H. pylori-specific cellular immune responses in recipient challenged and nonrecipient infected mice indicated a strong local restriction of the response in infected animals. The implications of these findings for the mechanism of protection and the development of peptide-based vaccination are discussed.

Local recall responses in the stomach involving reduced regulation and expanded help mediate vaccine‐induced protection against Helicobacter pylori in mice

“…1B). This is consistent with previous reports showing a critical role for CD4 1 T cells in vaccine-induced protection [15,26,27]. Interestingly, the carrier-vaccinated GK1.5 mice did not have reduced H. pylori colonisation compared with control mice, suggesting that this phenomenon is CD4 1 T-cell-dependent.…”

“…Levels of CD19 1 B cells in the blood were increased by 35% in all infected mice relative to naïve mice, probably in parallel with the systemic antibody response to both S. Typhimurium and H. pylori infection. The increase in numbers of B cells only reached significance in the case of the vaccinated group however, in accordance with previous observations that vaccinated mice have higher titres of H. pylori-specific antibody ( [29,30]). Interestingly no effects of vaccination or infection were observed in the local draining LN, the PGLN.…”

“…CD4 1 T cells are required for protection in animal models of vaccination, and adoptive transfer of these cells leads to reductions in colonisation in naïve recipients [14,15]. This observation has also been supported by data from a recent trial of a recombinant attenuated Salmonella enterica serovar Typhi (S. Typhi)-based H. pylori vaccine in human volunteers.…”

“…On the other, while a recent trial of a combined CagA/ NapA/alum formulation delivered via the intramuscular route was reported to induce strong antibody T-cell responses after four doses [10], most studies investigating mucosal vaccination approaches with live or protein-adjuvanted vaccines have been reported to induce weak, systemic immune responses in humans, as reflected by measurable antibody and T-cell responses [6,[11][12][13]. A better understanding of the immunological mechanisms underlying vaccination is therefore essential to aid development of an effective vaccine for humans.CD4 1 T cells are required for protection in animal models of vaccination, and adoptive transfer of these cells leads to reductions in colonisation in naïve recipients [14,15]. This observation has also been supported by data from a recent trial of a recombinant attenuated Salmonella enterica serovar Typhi (S. Typhi)-based H. pylori vaccine in human volunteers.…”

“…While controversy remains, the majority of studies have linked a strong Th1 cytokine response of CD4 1 T cells with protection against H. pylori [15,[33][34][35][36]. However, the key role of Th1 cells in inducing the secretion of IgG by activated plasma cells or the activation of macrophage killing appear to be dispensable for protection [37][38][39].…”