The anatomical origins of migratory dendritic cells in the intestine

The intestine is exposed to a vast array of harmless dietary antigen as well as an enormous community of commensal bacteria. Alongside this harmless antigen, pathogens can enter the body via the intestinal mucosal surface. The intestinal immune system must discriminate between pathogens and innocuous antigens. Dendritic cells (DCs), present in the small intestine (SI) and colon, are fundamental in controlling intestinal immune responses; they migrate to the mesenteric lymph node (MLN) and prime effector or regulatory T cells. Furthermore, DCs direct the immune response in the gut-associated lymphoid tissues (GALT), the Peyer’s patches (PP) and isolated lymphoid follicles (ILFs). The aim of this work was to determine the anatomical origins of DCs in the MLN. First, the anatomical organisation of lymphatic vessels draining to the MLN from the SI and colon was investigated. Second, DC migration in mice lacking specific GALT was explored. Finally, the migration of DCs from PPs to the MLN was investigated. To achieve these aims, DC migration was studied using a variety of labelling methods, mice that lacked specific GALT were employed, and surgical procedures were used to collect DCs from the thoracic duct. Here, I demonstrate the anatomical segregation of DCs that migrate to the MLN from the SI and colon. This was reflected in differences in DC subset composition and antigen presentation in the SI and colon-draining nodes of the MLN. Separate analysis of MLN nodes will allow a more refined understanding of intestinal immune responses. All but one DC subset, CD103-CD11b- DCs, were still present in pseudo-afferent lymph from mice lacking both PPs and ILFs. This subset is therefore likely to originate from either PPs or ILFs. Surprisingly, CD103+CD8α+ DCs were present in these mice, showing that many CD8α+ DCs were resident in the lamina propria and are not limited to lymphoid tissue. Four DC subsets are able to migrate from the intestine in PP-null mice, suggesting that CD103-CD11b- DCs migrate specifically from ILFs. I then demonstrated that DCs migrate from PPs to the MLN. These migrating PP DCs expanded in response to a DC specific growth factor and their migration depended on CCR7 and S1P. These cells may play an important role in driving immune responses in the MLN and their manipulation could lead to advances in controlling intestinal immune responses

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice