Helicobacter pylori Deregulates T and B Cell Signaling to Trigger Immune Evasion

Abstract

Helicobacter pylori is a prevalent human pathogen that successfully establishes chronic infection, which leads to clinically significant gastric diseases including chronic gastritis, peptic ulcer disease (PUD), and gastric cancer (GC). H. pylori is able to produce a persistent infection due in large part to its ability to hijack the host immune response. The host adaptive immune response is activated to strategically and specifically attack pathogens and normally clears them from the infected host. Since B and T lymphocytes are central mediators of adaptive immunity, in this chapter we review their development and the fundamental mechanisms regulating their activation in order to understand how some of the normal processes are subverted by H. pylori. In this review, we place particular emphasis on the CD4⁺ T cell responses, their subtypes, and regulatory mechanisms because of the expanding literature in this area related to H. pylori. T lymphocyte differentiation and function are finely orchestrated through a series of cell-cell interactions, which include immune checkpoint receptors. Among the immune checkpoint receptor family, there are some with inhibitory properties that are exploited by tumor cells to facilitate their immune evasion. Gastric epithelial cells (GECs), which act as antigen-presenting cells (APCs) in the gastric mucosa, are induced by H. pylori to express immune checkpoint receptors known to sway T lymphocyte function and thus circumvent effective T effector lymphocyte responses. This chapter reviews these and other mechanisms used by H. pylori to interfere with host immunity in order to persist.

Keywords: Co-inhibitory receptors; Immune checkpoint regulators; Immune evasion; Lymphocyte development; Reprogramming.

Fig.1

Schematic representation of lymphocyte differentiation and migration to gastric tissue. Bone marrow host hematopoietic stem cells (HSC) that progressively differentiate to rise to common lymphoid progenitors (CLP). CLPs differentiate into progenitor B cells (Pro-B cells) and double-negative (DN) thymocyte progenitors. Pro-B cells remain in bone marrow and differentiate into immature B cells that turn into mature B cells once they migrate to secondary lymphoid organs (i.e., lymph nodes and spleen). The CLP that migrate to the thymus commit to either natural killer (NK) cells or T lymphocyte lineage becoming γδ T lymphocytes or double-negative DN thymocytes. DN thymocytes undergo negative selection and only immature single positive cells survive to become CD4⁺ or CD8⁺ T lymphocytes capable of migrating to secondary lymphoid organs. Lymphoid cells are eventually recruited to gastric infected tissue where they become antibody-producing cells (B cells, plasmocytes) and CD4⁺ T lymphocytes differentiate into subsets depending on environmental cues

Fig. 2

Co-stimulatory and co-inhibitory receptors and their ligands. These molecules are also known as members of the B7-CD28 superfamily or immune checkpoint regulators because they affect T cell activity

Fig. 3

CD4⁺ T cell subsets. Upon activation, naïve CD4⁺ T cells differentiate following specific paths depending on environmental cues, which include distinct cytokines. As part of their differentiation, they express characteristic transcription factors or “master regulators” that determine their respective phenotypic differences and the cytokines that they produce

Fig. 4

H. pylori upregulate the expression of CD80 and IL-10 production via TLRs on B cells. B cells exposed to H. pylori upregulate receptors and cytokines that then promote Treg cell differentiation

Fig. 5

H. pylori CagA and peptidoglycan translocated by the type IV secretion system into GECs promote a suppressive environment. H. pylori CagA and peptidoglycan injected into GECs lead to a reduction of B7-H2 expression by activating the p70 S6 kinase pathway. H. pylori CagA also promotes PD-L1 (B7-H1) expression by GECs. Both of these responses combined promote a suppressive environment because the ICOS-L–ICOS interaction is critical for Th17 cell development, maintenance, and function and in the absence of the interaction Th17, cells fail to develop. PD-L1 provides inhibitory signals for effector Th cells and promotes differentiation of Treg cells (Lina et al. 2013)