Helicobacter pylori Dampens HLA-II Expression on Macrophages via the Up-Regulation of miRNAs Targeting CIITA

Abstract

Macrophages have a major role in infectious and inflammatory diseases, and the available data suggest that Helicobacter pylori persistence can be explained in part by the failure of the bacterium to be killed by professional phagocytes. Macrophages are cells ready to kill the engulfed pathogen, through oxygen-dependent and-independent mechanisms; however, their killing potential can be further augmented by the intervention of T helper (Th) cells upon the specific recognition of human leukocyte antigen (HLA)-II-peptide complexes on the surface of the phagocytic cells. As it pertains to H. pylori, the bacterium is engulfed by macrophages, but it interferes with the phagosome maturation process leading to phagosomes with an altered degradative capacity, and to megasomes, wherein H. pylori resists killing. We recently showed that macrophages infected with H. pylori strongly reduce the expression of HLA-II molecules on the plasma membrane and this compromises the bacterial antigen presentation to Th lymphocytes. In this work, we demonstrate that H. pylori hampers HLA-II expression in macrophages, activated or non-activated by IFN-γ, by down-regulating the expression of the class II major histocompatibility complex transactivator (CIITA), the "master control factor" for the expression of HLA class II genes. We provided evidence that this effect relies on the up-regulation of let-7f-5p, let-7i-5p, miR-146b-5p, and-185-5p targeting CIITA. MiRNA expression analysis performed on biopsies from H. pylori-infected patients confirmed the up-regulation of let-7i-5p, miR-146b-5p, and-185-5p in gastritis, in pre-invasive lesions, and in gastric cancer. Taken together, our results suggest that specific miRNAs may be directly involved in the H. pylori infection persistence and may contribute to confer the risk of developing gastric neoplasia in infected patients.

The Many Faces of CD4+ T Cells: Immunological and Structural Characteristics

“…CD4 + T cells are key players in the adaptive immune response. Following selection and maturation in the thymus, naïve CD4 + T cells migrate to the periphery where they survey for antigens displayed by human leukocyte antigen class II (HLA-II) molecules present on the surface of professional antigen presenting cells (APCs) [ 1 ], such as Dendritic cells (DCs) [ 2 ], B cells [ 3 ], macrophages [ 4 ], CD4 + T cells and airway and intestinal epithelial cells [ 5 ]. HLA-II molecules are composed of an alpha (α) and beta (β) chain ( Figure 1 ), anchored into the cell membrane, that together form the peptide (p) binding groove [ 1 ] ( Figure 1 A,B).…”

Immunopeptidomics for next-generation bacterial vaccine development

“…Similarly, other PTMs, such as formylation or palmitoylation (Box 3), can be found on bacterial immunopeptides, and even host cell-derived immunopeptides might display altered modifications during infection [66]. Bacterial infection can also interfere with host cell antigen presentation [80,100,101], and together with PTMs, such immunomodulatory processes should be considered in future immunopeptidomics studies. Finally, even though immunopeptidomics typically requires large amounts of starting material, recent innovations have allowed downscaling to ca.…”

Review ‐ Helicobacter, inflammation, immunology and vaccines

“…This was dependent on upregulation of miRNAs let‐7f‐5p, let‐7i‐5p, miR‐146b‐5p, and ‐185‐5p. These miRNAs were increased in mucosal biopsies from gastritis patients, suggesting their role in immune evasion 23 . Arnold et al showed that BATF3‐dependent CD103 + DCs are required for induction of gastric Th1 responses to H pylori in mice, and for recruitment of peripherally induced Tregs to the infected mucosa.…”