Owing to the importance of dendritic cells (DC) in the induction and control of immunity, an understanding of their biology is central to the development of potent immunotherapies for cancer, chronic infections, autoimmune disease, and induction of transplantation tolerance. This review surveys the heterogeneity of DC with regards to their phenotype and developmental origin, and how they initiate, modify and regulate the immune response, with emphasis on their maturation, migration, antigen-presentation and interaction with T cells and other immune cells. Much of this knowledge is obtained through research on murine DC. Research on human DC has been hampered by limitations associated with in vitro assays and limited access to human tissues. New approaches on human DC research are required in order to develop novel strategies for the treatment of microbial infections, the control of graft rejection, and the improvement of DC-based immunotherapeutic protocols for autoimmunity, allergy, and cancer.
Tuberculosis (TB) is the main cause of mortality among all infectious diseases. The presentation of lipids by CD1b molecules and the interactions of the CD1b-lipid complexes with the immune receptors are important for the understanding of the immune response to Mycobacterium tuberculosis (Mtb), and to develop TB control methods. A specific domain antibody (dAbk11) recognizing the complex of CD1b with Mtb sulphoglycolipid (Ac2SGL) had been previously developed. In order to study the interactions of dAbk11 with Ac2SGL:CD1b, the conformation of Ac2SGL within CD1b was first modelled. The orientation of dAbκ11 with Ac2SGL:CD1b was then predicted by a docking experiment and the complex was sampled using molecular dynamics simulation. Data showed that dAbκ11 Tyr32 OH plays a decisive role in interacting with Ac2SGL alkyl tail HO17. The binding free energy calculation showed that Ac2SGL establish strong hydrophobic interactions with dAbκ11. The model also predicted a higher affinity for the natural sulfoglycolipid (Ac2SGL) than the synthetic analogue (SGL12), which was supported by the ELISA data. These results shed light on the likely mechanism of interactions between Ac2SGL:CD1b and dAbκ11, thus making possible to envision the strategies for dAbκ11 optimization for possible future applications.
Coeliac disease (CD) is an inflammatory disorder of the small intestine. It includes aberrant adaptive immunity with presentation of CD toxic gluten peptides by HLA-DQ2 or DQ8 molecules to gluten-sensitive T cells. A ω-gliadin/C-hordein peptide (QPFPQPEQPFPW) and a rye-derived secalin peptide (QPFPQPQQPIPQ) were proposed to be toxic in CD, as they yielded positive responses when assessed with peripheral blood T-cell clones derived from individuals with CD. We sought to assess the immunogenicity of the candidate peptides using gluten-sensitive T-cell lines obtained from CD small intestinal biopsies. We also sought to investigate the potential cross-reactivity of wheat gluten-sensitive T-cell lines with peptic-tryptic digested barley hordein (PTH) and rye secalin (PTS). Synthesised candidate peptides were deamidated with tissue transglutaminase (tTG). Gluten-sensitive T-cell lines were generated by culturing small intestinal biopsies from CD patients with peptic-tryptic gluten (PTG), PTH or PTS, along with autologous PBMCs for antigen presentation. The stimulation indices were determined by measuring the relative cellular proliferation via incorporation of (3) H-thymidine. The majority of T-cell lines reacted to the peptides studied. There was also cross-reactivity between wheat gluten-sensitive T-cell lines and the hordein, gliadin and secalin peptides. PTH, PTS, barley hordein and rye secalin-derived CD antigen-sensitive T-cell lines showed positive stimulation with PTG. ω-gliadin/C-hordein peptide and rye-derived peptide are immunogenic to gluten-sensitive T-cell lines and potentially present in wheat, rye and barley. Additional CD toxic peptides may be shared.
Dengue virus (DV) infection demonstrates an intriguing virus-induced intracellular membrane alteration that results in the augmentation of major histocompatibility complex (MHC) class I-restricted antigen presentation. As oppose to its biological function in attracting CD8(+) T-cells, this phenomenon appears to facilitate the immune evasion. However, the molecular events that attribute to the dysregulation of the antigen presenting mechanism (APM) by DV remain obscure. In this study, we aimed to characterize the host cell APM upon infection with all serotypes of whole DV. Cellular RNA were isolated from infected cells and the gene expressions of LMP2, LMP7, TAP1, TAP2, TAPBP, CALR, CANX, PDIA3, HLA-A and HLA-B were analyzed via quantitative PCR. The profiles of the gene expression were further validated. We showed that all four DV serotypes modulate host APM at the proteasomal level with DV2 showing the most prominent expression profile.
Deep understanding of the genomic and immunological differences between Chinese and Western lung cancer patients is of great importance for target therapy selection and development for Chinese patients. Here we report an extensive molecular and immune profiling study of 245 Chinese patients with non-small cell lung cancer. Tumor-infiltrating lymphocyte estimated using immune cell signatures is found to be significantly higher in adenocarcinoma (ADC, 72.5%) compared with squamous cell carcinoma (SQCC, 54.4%). The correlation of genomic alterations with immune signatures reveals that low immune infiltration was associated with EGFR mutations in ADC samples, PI3K and/or WNT pathway activation in SQCC. While KRAS mutations are found to be significantly associated with T cell infiltration in ADC samples. The SQCC patients with high antigen presentation machinery and cytotoxic T cell signature scores are found to have a prolonged overall survival time.