Classical Flt3L-dependent dendritic cells control immunity to protein vaccine

DCs are critical for initiating immunity. The current paradigm in vaccine biology is that DCs migrating from peripheral tissue and classical lymphoid-resident DCs (cDCs) cooperate in the draining LNs to initiate priming and proliferation of T cells. Here, we observe subcutaneous immunity is Fms-like tyrosine kinase 3 ligand (Flt3L) dependent. Flt3L is rapidly secreted after immunization; Flt3 deletion reduces T cell responses by 50%. Flt3L enhances global T cell and humoral immunity as well as both the numbers and antigen capture capacity of migratory DCs (migDCs) and LN-resident cDCs. Surprisingly, however, we find immunity is controlled by cDCs and actively tempered in vivo by migDCs. Deletion of Langerin+ DC or blockade of DC migration improves immunity. Consistent with an immune-regulatory role, transcriptomic analyses reveals different skin migDC subsets in both mouse and human cluster together, and share immune-suppressing gene expression and regulatory pathways. These data reveal that protective immunity to protein vaccines is controlled by Flt3Ldependent, LN-resident cDCs

Erratum: Flt3L dependence helps define an uncharacterized subset of murine cutaneous dendritic cells

[No abstract available

Flt3L dependence helps define an uncharacterized subset of murine cutaneous dendritic cells

Skin-derived dendritic cells (DCs) are potent antigen-presenting cells with critical roles in both adaptive immunity and tolerance to self. Skin DCs carry antigens and constitutively migrate to the skin-draining lymph nodes (LNs). In mice, Langerin-CD11b- dermal DCs are a low-frequency, heterogeneous, migratory DC subset that traffics to LNs (Langerin-CD11b- migDCs). Here, we build on the observation that Langerin-CD11b- migDCs are Fms-like tyrosine kinase 3 ligand (Flt3L) dependent and strongly Flt3L responsive, which may relate them to classical DCs. Examination of DC capture of FITC from painted skin, DC isolation from skin explant culture, and from the skin of CCR7 knockout mice, which accumulate migDCs, demonstrate these cells are cutaneous residents. Langerin-CD11b- Flt3L-responsive DCs are largely CD24(+) and CX 3 CR1 low and can be depleted from Zbtb46-DTR mice, suggesting classical DC lineage. Langerin-CD11b- migDCs present antigen with equal efficiency to other DC subsets ex vivo, including classical CD8α cDCs and Langerin+CD103+ dermal DCs. Finally, transcriptome analysis suggests a close relationship with other skin DCs, and a lineage relationship with other classical DCs. This work demonstrates that Langerin- CD11b- dermal DCs, a previously overlooked cell subset, may be an important contributor to the cutaneous immune environment

Shared decision making in consultations for hypertension:Qualitative study in general practice

Abstract Background Hypertension is mainly managed in primary care. Shared decision making is widely recommended as an approach to treatment decision making. However, no studies have investigated; in detail, what happens during primary care consultations for hypertension. Aim To understand patients’ and clinicians’ experience of shared decision making for hypertension in primary care, in order to propose how it might be better supported. Design Longitudinal qualitative study. Setting Five general practices in south‐west England. Method Interviews with a purposive sample of patients with hypertension, and with the health‐care practitioners they consulted, along with observations of clinical consultations, for up to 6 appointments. Interviews and consultations were audio‐recorded and observational field notes taken. Data were analysed thematically. Results Forty‐six interviews and 18 consultations were observed, with 11 patients and nine health‐care practitioners (five GPs, one pharmacist and three nurses). Little shared decision making was described by participants or observed. Often patients’ understanding of their hypertension was limited, and they were not aware there were treatment choices. Consultations provided few opportunities for patients and clinicians to reach a shared understanding of their treatment choices. Opportunities for patients to engage in choices were limited by structured consultations and the distribution of decisions across consultations. Conclusion For shared decision making to be better supported, consultations need to provide opportunities for patients to learn about their condition, to understand that there are treatment choices, and to discuss these choices with clinicians. Patient or Public Contribution A patient group contributed to the design of this study

Flt3L-dependence helps define an uncharacterized subset of murine cutaneous dendritic cells

Skin-derived dendritic cells (DC) are potent antigen presenting cells with critical roles in both adaptive immunity and tolerance to self. Skin DC carry antigens and constitutively migrate to the skin draining lymph nodes (LN). In mice, Langerin-CD11b− dermal DC are a low-frequency, heterogeneous, migratory DC subset that traffic to LN (Langerin-CD11b-migDC). Here, we build on the observation that Langerin-CD11b− migDC are Fms-like tyrosine kinase 3 ligand (Flt3L) dependent and strongly Flt3L responsive, which may relate them to classical DCs. Examination of DC capture of FITC from painted skin, DC isolation from skin explant culture, and from the skin of CCR7 knockout mice which accumulate migDC, demonstrate these cells are cutaneous residents. Langerin-CD11b-Flt3L responsive DC are largely CD24(+) and CX3CR1low and can be depleted from Zbtb46-DTR mice, suggesting classical DC lineage. Langerin-CD11bmigDC present antigen with equal efficiency to other DC subsets ex vivo including classical CD8α cDC and Langerin+CD103+ dermal DC. Finally, transcriptome analysis suggests a close relationship to other skin DC, and a lineage relationship to other classical DC. This work demonstrates that Langerin- CD11b− dermal DC, a previously overlooked cell subset, may be an important player in the cutaneous immune environment

“Who does this patient belong to?” Boundary work and the re/making of (NSTEMI) heart attack patients

This ethnography within ten English and Welsh hospitals explores the significance of boundary work and the impacts of this work on the quality of care experienced by heart attack patients who have suspected non–ST segment elevation myocardial infarction (NSTEMI) /non-ST elevation acute coronary syndrome. Beginning with the initial identification and prioritisation of patients, boundary work informed negotiations over responsibility for patients, their transfer and admission to different wards, and their access to specific domains in order to receive diagnostic tests and treatment. In order to navigate boundaries successfully and for their clinical needs to be more easily recognised by staff, a patient needed to become a stable boundary object. Ongoing uncertainty in fixing their clinical classification, was a key reason why many NSTEMI patients faltered as boundary objects. Viewing NSTEMI patients as boundary objects helps to articulate the critical and ongoing process of classification and categorisation in the creation and maintenance of boundary objects. We show the essential, but hidden, role of boundary actors in making and re-making patients into boundary objects. Physical location was critical and the parallel processes of exclusion and restriction of boundary object status can lead to marginalisation of some patients and inequalities of care.NIHR Research for Patient Benefi