Cell shape sensing licenses dendritic cells for homeostatic migration to lymph nodes.

Immune cells experience large cell shape changes during environmental patrolling because of the physical constraints that they encounter while migrating through tissues. These cells can adapt to such deformation events using dedicated shape-sensing pathways. However, how shape sensing affects immune cell function is mostly unknown. Here, we identify a shape-sensing mechanism that increases the expression of the chemokine receptor CCR7 and guides dendritic cell migration from peripheral tissues to lymph nodes at steady state. This mechanism relies on the lipid metabolism enzyme cPLA2, requires nuclear envelope tensioning and is finely tuned by the ARP2/3 actin nucleation complex. We also show that this shape-sensing axis reprograms dendritic cell transcription by activating an IKKß-NF-κB-dependent pathway known to control their tolerogenic potential. These results indicate that cell shape changes experienced by immune cells can define their migratory behavior and immunoregulatory properties and reveal a contribution of the physical properties of tissues to adaptive immunity.

Homeostatic IL-13 in healthy skin directs dendritic cell differentiation to promote TH2 and inhibit TH17 cell polarization.

The signals driving the adaptation of type 2 dendritic cells (DC2s) to diverse peripheral environments remain mostly undefined. We show that differentiation of CD11blo migratory DC2s-a DC2 population unique to the dermis-required IL-13 signaling dependent on the transcription factors STAT6 and KLF4, whereas DC2s in lung and small intestine were STAT6-independent. Similarly, human DC2s in skin expressed an IL-4 and IL-13 gene signature that was not found in blood, spleen and lung DCs. In mice, IL-13 was secreted homeostatically by dermal innate lymphoid cells and was independent of microbiota, TSLP or IL-33. In the absence of IL-13 signaling, dermal DC2s were stable in number but remained CD11bhi and showed defective activation in response to allergens, with diminished ability to support the development of IL-4+GATA3+ helper T cells (TH), whereas antifungal IL-17+RORγt+ TH cells were increased. Therefore, homeostatic IL-13 fosters a noninflammatory skin environment that supports allergic sensitization.

The Kinase IKKß Regulates a STING- and NF-κB-Dependent Antiviral Response Pathway in Drosophila.

Antiviral immunity in Drosophila involves RNA interference and poorly characterized inducible responses. Here, we showed that two components of the IMD pathway, the kinase dIKKß and the transcription factor Relish, were required to control infection by two picorna-like viruses. We identified a set of genes induced by viral infection and regulated by dIKKß and Relish, which included an ortholog of STING. We showed that dSTING participated in the control of infection by picorna-like viruses, acting upstream of dIKKß to regulate expression of Nazo, an antiviral factor. Our data reveal an antiviral function for STING in an animal model devoid of interferons and suggest an evolutionarily ancient role for this molecule in antiviral immunity.

How type-2 dendritic cells induce Th2 differentiation: Instruction, repression, or fostering T cell-T cell communication?

Allergic disease is caused by the activation of allergen-specific CD4+ type-2 T follicular helper cells (Tfh2) and T helper 2 (Th2) effector cells that secrete the cytokines IL-4, IL-5, IL-9, and IL-13 upon allergen encounter, thereby inducing IgE production by B cells and tissue inflammation. While it is accepted that the priming and differentiation of naïve CD4+ T cells into Th2 requires allergen presentation by type 2 dendritic cells (DC2s), the underlying signals remain unidentified. In this review we focus on the interaction between allergen-presenting DC2s and naïve CD4+ T cells in lymph node (LN), and the potential mechanisms by which DC2s might instruct Th2 differentiation. We outline recent advances in characterizing DC2 development and heterogeneity. We review mechanisms of allergen sensing and current proposed mechanisms of Th2 differentiation, with specific consideration of the role of DC2s and how they might contribute to each mechanism. Finally, we assess recent publications reporting a detailed analysis of DC-T cell interactions in LNs and how they support Th2 differentiation. Together, these studies are starting to shape our understanding of this key initial step of the allergic immune response.

IL-13 in dermal type-2 dendritic cell specialization: From function to therapeutic targeting.

Skin functions as a barrier protecting the host against physical, thermal, chemical changes as well as microbial insults. The skin is populated by several immune cell types that are crucial to host defense and to maintain self-tolerance as well as equilibrium with beneficial microbiota. Conventional dendritic cells (cDCs) are antigen-presenting cells that patrol the skin and all other nonlymphoid tissues for self or foreign antigens, and then migrate to draining lymph nodes to initiate T-cell responses. This review article describes recent developments on skin cDC specialization, focusing on the role of IL-13, a cytokine essential to allergic immune responses that is also secreted at steady state by type-2 innate lymphoid cells in healthy skin, and is required for dermal cDC differentiation. Furthermore, we contextualize how different therapeutics that block IL-13 signaling and were recently approved for the treatment of atopic dermatitis might affect cDCs in human skin.

Thymic stromal lymphopoietin drives the development of IL-13+ Th2 cells.

T helper 2 (Th2) cells are pivotal in the development of allergy. Allergen exposure primes IL-4+ Th2 cells in lymph node, but production of effector cytokines including IL-5 and IL-13 is thought to require additional signals from antigen and the environment. Here we report that a substantial proportion of naive CD4+ T cells in spleen and lymph node express receptors for the epithelium-derived inflammatory cytokine thymic stromal lymphopoietin (TSLP). Culture of naive CD4+ T cells in anti-(a)CD3, aCD28, and TSLP-supplemented Th2 conditions enabled the development of a unique population of IL-13-single positive (IL-13-SP) CD4+ T cells; TSLP and Th2 conditions were both required for their development. Sorting experiments revealed that IL-13-SP Th2 cells originated from IL-4-negative precursors and coexpressed transcripts for the Th2 cytokines IL-5 and IL-9. In vivo, high TSLP levels acted directly on CD4+ T cells to induce the development of IL-13-SP and IL-4+IL-13+ double-positive populations in lymph node. These cells were phenotypically similar to Th2 effector cells and were CXCR5lowPD1low and expressed low levels of Bcl6 and Il21 transcripts and high levels of Gata3, Il3, and Il5 Our findings suggest a role of TSLP in directly promoting Th2 cell effector function and support the notion of TSLP as a key driver of Th2 inflammation.

Dendritic cells in Th2 immune responses and allergic sensitization.

Allergic responses are characterized by the activation of a specific subset of effector CD4+ T cells, the T-helper type 2 (Th2) cells, that respond to harmless environmental antigens causing inflammation and pathology. Th2 cells are also found in the context of parasite infections, where they can mediate parasite clearance and expulsion, and support tissue repair. The process that leads to the activation of Th2 cells in vivo is incompletely understood: while it has become clear that "conventional" dendritic cells are essential antigen-presenting cells for the initiation of Th2 immune responses, the molecules that are expressed by dendritic cells exposed to allergens, and the mediators that are produced as a consequence and signal to naïve CD4+ T cells to promote their development into effector Th2, remain to be defined. Here we summarize recent developments in the identification of the dendritic cell subsets involved in Th2 responses, review potential mechanisms proposed to explain the generation of these immune responses, and discuss the direct and indirect signals that condition dendritic cells to drive the development of Th2 responses during allergen or parasite exposure.

Genetic regulation of antibody responsiveness to immunization in substrains of BALB/c mice.

Antibody-mediated immunity is highly protective against disease. The majority of current vaccines confer protection through humoral immunity, but there is high variability in responsiveness across populations. Identifying immune mechanisms that mediate low antibody responsiveness may provide potential strategies to boost vaccine efficacy. Here, we report diverse antibody responsiveness to unadjuvanted as well as adjuvanted immunization in substrains of BALB/c mice, resulting in high and low antibody response phenotypes. Furthermore, these antibody phenotypes were not affected by changes in environmental factors such as the gut microbiota composition. Antigen-specific B cells following immunization had a marked difference in capability to class switch, resulting in perturbed IgG isotype antibody production. In vitro, a B-cell intrinsic defect in the regulation of class-switch recombination was identified in mice with low IgG antibody production. Whole genome sequencing identified polymorphisms associated with the magnitude of antibody produced, and we propose candidate genes that may regulate isotype class-switching capability. This study highlights that mice sourced from different vendors can have significantly altered humoral immune response profiles, and provides a resource to interrogate genetic regulators of antibody responsiveness. Together these results further our understanding of immune heterogeneity and suggest additional research on the genetic influences of adjuvanted vaccine strategies is warranted for enhancing vaccine efficacy.