Gastric Subserous Vaccination With Helicobacter pylori Vaccine: An Attempt to Establish Tissue-Resident CD4+ Memory T Cells and Induce Prolonged Protection

Abstract

Tissue-resident memory T (Trm) cells are enriched at the sites of previous infection and required for enhanced protective immunity. However, the emergence of Trm cells and their roles in providing protection are unclear in the field of Helicobacter pylori ( H. pylori ) vaccinology. Here, our results suggest that conventional vaccine strategies are unable to establish a measurable antigen (Ag)-specific memory cell pool in stomach; in comparison, gastric subserous injection of mice with micro-dose of Alum-based H. pylori vaccine can induce a pool of local CD4+ Trm cells. Regional recruitment of Ag-specific CD4+ T cells depends on the engagement of Ag and adjuvant-induced inflammation. Prior subcutaneous vaccination enhanced this recruitment. A stable pool of Ag-specific CD4+ T cells can be detected for 240 days. Two weeks of FTY720 administration in immune mice suggests that these cells do not experience the recirculation. Immunohistochemistry results show that close to the vaccination site, abundant CD4+T cells locate on epithelial niches, independent of lymphocyte cluster. Paradigmatically, Ag-specific CD4+ T cells with a phenotype of CD69+CD103- are preferential on lymphocytes isolated from epithelium. Upon Helicobacter infection, CD4+ Trm cells orchestrate a swift recall response with the recruitment of circulating antigen-specific Th1/Th17 cells to trigger a tissue-wide pathogen clearance. This study investigates the vaccine-induced gastric CD4+ Trm cells in a mice model, and highlights the need for designing a vaccine strategy against H. pylori by establishing the protective CD4+ Trm cells.

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

“…Using a new strategy for mucosal vaccination, Stary et al showed that IFN-γ producing CD4 + T RM are pivotal for protection against Chlamydia trachomatis [124,128]. Similar findings have been reported for genital tract herpes simplex virus (HSV) vaccination [120], and gastric subserous vaccination with Helicobacter pylori vaccine [129]. Therefore, identification of mechanisms which promote the generation and retention of CD4 + T RM should be further explored for development of more effective vaccines against a range of human pathogens [130].…”

Vaccine‐induced gastric CD4+ tissue‐resident memory T cells proliferate in situ to amplify immune response against Helicobacter pylori insult

“…But it was less known about CD4 + TRM cells, which might attribute to CD4 + TRM cells, which are less efficiently generated in present mouse models . Fortunately, our previous study demonstrated that CD4 + TRM cells could efficiently generate by vaccination in GSL and protect the stomach from the H pylori infection, but it did not distinguish vaccine‐induced CD4 + TRM cells so that it could not persuasively explore whether the CD4 + TRM cells themselves can induce protective effect …”

“…The single‐cell suspension of the stomach was purified with 67%/44% Percoll gradients. After cells were collected, they were washed with 1 mL RPMI 1640 containing 10% FBS …”

“…Rather than other ways (such as p.o. and s.c.), vaccination in GSL induced rapid and long‐term protection against H pylori infection . However, the limitation was that Alum‐based H pylori vaccination in GSL led to granuloma and vaccine‐induced CD4 + TRM cells were regional.…”

Perivascular Lymphocyte Clusters Induced by Gastric Subserous Layer Vaccination Mediate Optimal Immunity against Helicobacter through Facilitating Immune Cell Infiltration and Local Antibody Response

“…In a previous study, we used vaccine composed of aluminum adjuvant and CCF (CCF, a recombinant Helicobacter pylori subunit vaccine, a dual-antigen epitope, and a dualadjuvant vaccine constructed as previously described [5]), to vaccinate the gastric subserous layer (GSL) of mice [6]. GSL vaccination-induced mucosal inflammation in the stomach and subsequently a pool of CD4 + tissue-resident T cells (CD4 + T RM ) were established in the epithelium.…”