Immune checkpoint blockade has revolutionized the treatment of multiple tumor types, including melanoma and nonmelanoma skin cancers. The use of immune checkpoint blockade is curtailed by tissue ...toxicities termed immune-related adverse events (irAEs), which occur most quickly and most often in the skin. We review the rationale for immune checkpoint blockade use, current agents, use in skin cancers, autoimmune manifestations in the skin, and considerations for predictive biomarkers and treatment options on the basis of skin pathogenesis. We also highlight major gaps in the field and the lack of preclinical modeling in the skin. A deeper understanding of irAE pathophysiology may help to uncouple toxicity and efficacy but mandates an interdisciplinary approach, including foundational skin immunology and autoimmune pathogenesis.
Brief exposure of skin to near-infrared (NIR) laser light has been shown to augment the immune response to intradermal vaccination and thus act as an immunologic adjuvant. Although evidence indicates ...that the NIR laser adjuvant has the capacity to activate innate subsets including dendritic cells (DCs) in skin as conventional adjuvants do, the precise immunological mechanism by which the NIR laser adjuvant acts is largely unknown. In this study we sought to identify the cellular target of the NIR laser adjuvant by using an established mouse model of intradermal influenza vaccination and examining the alteration of responses resulting from genetic ablation of specific DC populations. We found that a continuous wave (CW) NIR laser adjuvant broadly modulates migratory DC (migDC) populations, specifically increasing and activating the Lang
and CD11b
Lang
subsets in skin, and that the Ab responses augmented by the CW NIR laser are dependent on DC subsets expressing CCR2 and Langerin. In comparison, a pulsed wave NIR laser adjuvant showed limited effects on the migDC subsets. Our vaccination study demonstrated that the efficacy of the CW NIR laser is significantly better than that of the pulsed wave laser, indicating that the CW NIR laser offers a desirable immunostimulatory microenvironment for migDCs. These results demonstrate the unique ability of the NIR laser adjuvant to selectively target specific migDC populations in skin depending on its parameters, and highlight the importance of optimization of laser parameters for desirable immune protection induced by an NIR laser-adjuvanted vaccine.
The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. ...We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus.
BackgroundThe autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure inflames skin. Beneficial effects of ...anifrolumab (anti-interferon α/βreceptor (anti-IFNAR)) on lupus skin disease support a pathogenic role for IFN-I , but mechanistic understanding is limited. We have shown that Langerhans cell (LC) dysfunction contributes to photosensitivity. Healthy LCs act via a disintegrin and metalloprotease 17 (ADAM17) to release epidermal growth factor receptor (EGFR) ligands that limit UVR-induced keratinocyte apoptosis and photosensitivity. However, LC ADAM17 activity is reduced in non-lesional lupus model skin, and data point to reduced LC- mediated protection in human lupus. Here, we asked about the role of the IFN-rich lupus skin environment in LC dysfunction and the implications of this regulation for photosensitivity.MethodsGene expression patterns in non-lesional skin from human lupus and multiple murine models were examined. We used MRL/lpr, B6.Sle1yaa, and imiquimod models of lupus in in vivo studies to assess the role of IFN-I in LC ADAM17 dysfunction and photosensitivity.ResultsWe show a shared IFN-rich environment in non-lesional skin across human and murine model systems, that IFN-I inhibits LC ADAM17 activity, and that anti-IFNAR in lupus models restores LC ADAM17 function and reduces photosensitivity in EGFR and LC ADAM17- dependent manners. Reactive oxygen species (ROS) can mediate ADAM17 activity, and we show reduced LC ROS expression in lupus models that is restored by anti-IFNAR.ConclusionsOur findings suggest that IFN-I promotes photosensitivity by causing LC ADAM17 dysfunction and that anifrolumab ameliorates lupus skin disease at least in part by restoring LC function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a mechanism of action for anifrolumab in lupus.
T follicular helper cells contribute to the development of long-lasting humoral immunity by germinal center formation. Somatic hypermutation and affinity maturation take place in germinal centers ...leading to the generation of memory B cells and plasma cells. As such, T follicular helper cells impact immunodeficiencies, autoimmunity, and cancer. This necessitates further understanding of how T follicular helper cells are regulated in health and disease. The current study by Levin et al. builds on prior work to further substantiate a critical role for skin migratory dendritic cells and in particular Langerhans cells at governing T follicular helper and germinal center formation after intradermal immunization with HIV p24-coated polylactic acid nanoparticles.
In budding yeast, the Sec6/8p complex is essential for generating cell polarity by specifying vesicle delivery to the bud tip. We show that Sec6/8 homologs are components of a cytosolic, ∼17S complex ...in nonpolarized MDCK epithelial cells. Upon initiation of calcium-dependent cell–cell adhesion, ∼70% of Sec6/8 is rapidly (t
1/2 ≈ 3–6 hr) recruited to sites of cell–cell contact. In streptolysin-O-permeabilized MDCK cells, Sec8 antibodies inhibit delivery of LDL receptor to the basal-lateral membrane, but not p75
NTR to the apical membrane. These results indicate that lateral membrane recruitment of the Sec6/8 complex is a consequence of cell–cell adhesion and is essential for the biogenesis of epithelial cell surface polarity.
BackgroundPhotosensitivity is a common feature in systemic lupus erythematosus (SLE), is considered to be a major contributor to SLE skin disease, and can be associated with serious flares of ...systemic disease, but mechanistic understanding remains limited. Several lines of evidence including the finding of a type I interferon (IFN-I) signature in non-lesional skin, the potentiation of keratinocyte apoptosis by IFN-I, the importance of IFNAR in murine lupus model skin lesion development, and the improved skin scores in the clinical trials of anifrolumab (anti-IFNAR1) point to a pathogenic role for IFN-I in SLE skin disease. We recently showed that Langerhans cells (LCs) limit UVR-induced keratinocyte apoptosis and skin injury via ADAM17-mediated EGFR ligand activation and that reduced LC ADAM17 activity in two lupus models contributed to their photosensitivity. Non-lesional human SLE skin also showed evidence of a dysfunctional LC-keratinocyte axis; however, what causes LC dysfunction is not known. Here we test the hypothesis that IFN-I in the skin contributes to LC ADAM17 dysfunction and thus photosensitivity.MethodsTo assess IFN-I gene signature, microarray of non-lesional skin from human cutaneous LE and RNA sequencing of whole skin from lupus mouse models were performed. To quantify human and murine LC ADAM17 activity and expression, in vitro and ex vivo flow cytometric-based assays were conducted LCs. To assay photosensitivity, readouts of skin inflammation and cellular infiltrate were measured and characterized.ResultsWe show that non-lesional skin from human cutaneous LE and photosensitive MRL/lpr and B6.Sle1yaa mice all share IFN-I signatures and that IFN-I is sufficient to reduce human and murine LC ADAM17 activity independently of surface ADAM17 levels. IFN-I induced LC ADAM17 activity defects were abrogated with tofaticinib, a JAK kinase inhibitor approved for rheumatoid arthritis and other rheumatologic diseases. We further show that anti-IFNAR1 treatment prior to UVR exposure in lupus models restores LC ADAM17 activity and limits photosensitivity.ConclusionsTogether, our results suggest a model whereby the elevated IFN-I in non-lesional skin contributes to photosensitivity at least in part by causing LC ADAM17 dysfunction. The corollary is that anti-IFNAR has beneficial effects at least in part by correcting LC ADAM17 dysfunction.AcknowledgementsThis work was supported by National Institutes of Health R01AI079178 (TTL), the Lupus Research Alliance (TTL), the St. Giles Foundation (TTL) and AΩA Carolyn L. Kuckein Student Research Fellowship (TML).
Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states
. Here we identify the nuclear factor TOX as a crucial ...regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.
Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection
, but the host response at the lung tissue level is poorly understood. Here we performed single-nucleus ...RNA sequencing of about 116,000 nuclei from the lungs of nineteen individuals who died of COVID-19 and underwent rapid autopsy and seven control individuals. Integrated analyses identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, thereby providing insight into the biology of lethal COVID-19. The lungs from individuals with COVID-19 were highly inflamed, with dense infiltration of aberrantly activated monocyte-derived macrophages and alveolar macrophages, but had impaired T cell responses. Monocyte/macrophage-derived interleukin-1β and epithelial cell-derived interleukin-6 were unique features of SARS-CoV-2 infection compared to other viral and bacterial causes of pneumonia. Alveolar type 2 cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition into alveolar type 1 cells, resulting in impaired lung regeneration. Furthermore, we identified expansion of recently described CTHRC1
pathological fibroblasts
contributing to rapidly ensuing pulmonary fibrosis in COVID-19. Inference of protein activity and ligand-receptor interactions identified putative drug targets to disrupt deleterious circuits. This atlas enables the dissection of lethal COVID-19, may inform our understanding of long-term complications of COVID-19 survivors, and provides an important resource for therapeutic development.
APCs play a key role at initiating adaptive immune responses by presenting antigens to lymphocytes and DCs are professional APCs. It is critical to understand the differential antigen capture and ...presentation ability of different DC subsets, which is important for DC-targeted immunotherapy. In this section, we give a brief introduction to different antigen presentation pathways and introduce the key concept of cross-presentation, the major antigen presentation pathway used for anti-viral and anti-tumoral immune responses. CD205, a DC restricted receptor, is highly expressed on certain DCs subsets. We find CD205-mediated antigen uptake to be a useful model for studying antigen uptake and defects. These methods provide an introduction to CD205-mediated pre-clinical delivery of antigens to cross-presenting DCs, which can be adapted to the study of targeting to multiple receptors and other C-type lectins. This is a promising strategy to detect the antigen capture capacity and to study the key players orchestrating tolerance and immunity ex vivo.
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