Caroline L. Sokol

A mechanism for the initiation of allergen-induced T helper type 2 responses

Both metazoan parasites and simple protein allergens induce T helper type 2 (TH2) immune responses, but the mechanisms by which the innate immune system senses these stimuli are unknown. In addition, the cellular source of cytokines that control TH2 differentiation in vivo has not been defined. Here we showed that basophils were activated and recruited to the draining lymph nodes specifically in response to TH2–inducing allergen challenge. Furthermore, we demonstrate that the basophil was the accessory cell type required for TH2 induction in response to protease allergens. Finally, we show that basophils were directly activated by protease allergens and produced TH2-inducing cytokines, including interleukin 4 and thymic stromal lymphopoietin, which are involved in TH2 differentiation in vivo.

Chemokines and Chemokine Receptors: Positioning Cells for Host Defense and Immunity

Chemokines are chemotactic cytokines that control the migratory patterns and positioning of all immune cells. Although chemokines were initially appreciated as important mediators of acute inflammation, we now know that this complex system of approximately 50 endogenous chemokine ligands and 20 G protein-coupled seven-transmembrane signaling receptors is also critical for the generation of primary and secondary adaptive cellular and humoral immune responses. Recent studies demonstrate important roles for the chemokine system in the priming of naive T cells, in cell fate decisions such as effector and memory cell differentiation, and in regulatory T cell function. In this review, we focus on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the organismic level in homeostasis, in acute inflammation, and during the generation and regulation of adoptive primary and secondary immune responses in the lymphoid system and peripheral nonlymphoid tissue.

Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response

T helper type 2 (TH2)-mediated immune responses are induced after infection with multicellular parasites and can be triggered by a variety of allergens. The mechanisms of induction and the antigen-presenting cells involved in the activation of TH2 responses remain poorly defined, and the innate immune sensing pathways activated by parasites and allergens are largely unknown. Basophils are required for the in vivo induction of TH2 responses by protease allergens. Here we show that basophils also function as antigen-presenting cells. We show that although dendritic cells were dispensable for allergen-induced activation of TH2 responses in vitro and in vivo, antigen presentation by basophils was necessary and sufficient for this. Thus, basophils function as antigen-presenting cells for TH2 differentiation in response to protease allergens.

Role of basophils in the initiation of Th2 responses

Long appreciated for their role as Type-2 effector cells, basophils have recently come into the spotlight for their role in the initiation of Type-2 immunity. Via an assortment of different activation pathways, basophils produce cytokines such as IL-4 that promote Th2 differentiation. Furthermore, recent studies using different experimental systems have shown that basophils can act as antigen presenting cells both in vitro and in vivo. In addition, basophils shape the Type-2 immune response by guiding antibody production and the memory response.

Fas/Fas Ligand Deficiency Results in Altered Localization of Anti-Double-Stranded DNA B Cells and Dendritic Cells

Autoantibodies directed against dsDNA are found in patients with systemic lupus erythematosus as well as in mice functionally deficient in either Fas or Fas ligand (FasL) (lpr/lpr or gld/gld mice). Previously, an IgH chain transgene has been used to track anti-dsDNA B cells in both nonautoimmune BALB/c mice, in which autoreactive B cells are held in check, and MRL-lpr/lpr mice, in which autoantibodies are produced. In this study, we have isolated the Fas/FasL mutations away from the autoimmune-prone MRL background, and we show that anti-dsDNA B cells in Fas/FasL-deficient BALB/c mice are no longer follicularly excluded, and they produce autoantibodies. Strikingly, this is accompanied by alterations in the frequency and localization of dendritic cells as well as a global increase in CD4 T cell activation. Notably, as opposed to MRL-lpr/lpr mice, BALB-lpr/lpr mice show no appreciable kidney pathology. Thus, while some aspects of autoimmune pathology (e.g., nephritis) rely on the interaction of the MRL background with the lpr mutation, mutations in Fas/FasL alone are sufficient to alter the fate of anti-dsDNA B cells, dendritic cells, and T cells.

The Chemokine System in Innate Immunity

Chemokines are chemotactic cytokines that control the migration and positioning of immune cells in tissues and are critical for the function of the innate immune system. Chemokines control the release of innate immune cells from the bone marrow during homeostasis as well as in response to infection and inflammation. They also recruit innate immune effectors out of the circulation and into the tissue where, in collaboration with other chemoattractants, they guide these cells to the very sites of tissue injury. Chemokine function is also critical for the positioning of innate immune sentinels in peripheral tissue and then, following innate immune activation, guiding these activated cells to the draining lymph node to initiate and imprint an adaptive immune response. In this review, we will highlight recent advances in understanding how chemokine function regulates the movement and positioning of innate immune cells at homeostasis and in response to acute inflammation, and then we will review how chemokine-mediated innate immune cell trafficking plays an essential role in linking the innate and adaptive immune responses.

Airway Epithelial MyD88 Restores Control of Pseudomonas aeruginosa Murine Infection via an IL-1–Dependent Pathway

The opportunistic human pathogen Pseudomonas aeruginosa causes rapidly progressive and tissue-destructive infections, such as hospital-acquired and ventilator-associated pneumonias. Innate immune responses are critical in controlling P. aeruginosa in the mammalian lung, as demonstrated by the increased susceptibility of MyD88−/− mice to this pathogen. Experiments conducted using bone marrow chimeric mice demonstrated that radio-resistant cells participated in initiating MyD88-dependent innate immune responses to P. aeruginosa. In this study we used a novel transgenic mouse model to demonstrate that MyD88 expression by epithelial cells is sufficient to generate a rapid and protective innate immune response following intranasal infection with P. aeruginosa. MyD88 functions as an adaptor for many TLRs. However, mice in which multiple TLR pathways (e.g., TLR2/TLR4/TLR5) are blocked are not as compromised in their response to P. aeruginosa as mice lacking MyD88. We demonstrate that IL-1R signaling is an essential element of MyD88-dependent epithelial cell responses to P. aeruginosa infection.

Emerging functions of basophils in protective and allergic immune responses

Basophils that were long thought to have a redundant role in mast cells in the effector response to allergens and parasites are now being recognized to have important roles in the regulation of adaptive immune responses. Recent data have revealed their role in the initiation of the T helper cell 2 (Th2)-mediated immune response. Not only do basophils guide the Th1–Th2 balance by providing an early source of crucial Th2-skewing cytokines, interleukin (IL)-4 and thymic stromal lymphopoietin, but recent findings have also illustrated their capacity to function as antigen-presenting cells. Thus, basophils activate and instruct naive CD4 T cells, and guide their development into Th2 cells. Not only do basophils directly interact with T cells, but new insights have illustrated that they may also directly guide antibody responses in both the primary and memory responses. These and other studies have illustrated the emerging role of basophils in the regulation of type 2 immunity.

Single-Cell RNA Sequencing of Lymph Node Stromal Cells Reveals Niche-Associated Heterogeneity

SUMMARY Stromal cells (SCs) establish the compartmentalization of lymphoid tissues critical to the immune response. However, the full diversity of lymph node (LN) SCs remains undefined. Using droplet‐based single‐cell RNA sequencing, we identified nine peripheral LN non‐endothelial SC clusters. Included are the established subsets, Ccl19hi T‐zone reticular cells (TRCs), marginal reticular cells, follicular dendritic cells (FDCs), and perivascular cells. We also identified Ccl19lo TRCs, likely including cholesterol‐25‐hydroxylase+ cells located at the T‐zone perimeter, Cxcl9+ TRCs in the T‐zone and interfollicular region, CD34+ SCs in the capsule and medullary vessel adventitia, indolethylamine N‐methyltransferase+ SCs in the medullary cords, and Nr4a1+ SCs in several niches. These data help define how transcriptionally distinct LN SCs support niche‐restricted immune functions and provide evidence that many SCs are in an activated state. Graphical Abstract Figure. No Caption available. HighlightsSingle‐cell RNA sequencing of lymph node stromal cells reveals nine clustersKnown subsets TRCs, MRCs, FDCs, and perivascular cells identifiedFive additional stromal cell clusters identified and anatomical locations determinedTwo clusters, Cxcl9+ TRCs and Nr4a1+ SCs, are defined by activation signatures &NA; Lymph node stromal cells support diverse processes, but bulk assessments obscure their niche‐specific functions. Rodda et al. identify transcriptional profiles for nine lymph node stromal cell clusters using single‐cell RNA sequencing, validate subset markers in situ, and suggest niche‐restricted functions.

Ceftaroline Desensitization Procedure in a Pregnant Patient With Multiple Drug Allergies

Validated skin testing is lacking for many drugs, including ceftaroline. The cross-reactivity between ceftaroline and other β-lactam antibiotics is unknown. We report a case of a pregnant patient with cystic fibrosis and multiple drug allergies who required ceftaroline for methicillin-resistant Staphylococcus aureus pneumonia and underwent an uncomplicated empiric desensitization procedure.