ABSTRACT
Naive CD4+ T cells in specific pathogen-free (SPF) mice are characterized by transcriptional heterogeneity and subpopulations distinguished by the expression of quiescence, the extracellular matrix (ECM) and cytoskeleton, type I interferon (IFN-I) response, memory-like, and T cell receptor (TCR) activation genes. We demonstrate that this constitutive heterogeneity, including the presence of the IFN-I response cluster, is commensal independent insofar as being identical in germ-free and SPF mice. By contrast, Nippostrongylus brasiliensis infection altered this constitutive heterogeneity. Naive T cell-intrinsic transcriptional changes acquired during helminth infection correlated with and accounted for decreased immunization response to an unrelated antigen. These compositional and functional changes were dependent variables of helminth infection, as they disappeared at the established time point of its clearance in mice. Collectively, our results indicate that the naive T cell pool is subject to dynamic transcriptional changes in response to certain environmental cues, which in turn permutes the magnitude of the immune response.
Subject(s)
CD4-Positive T-Lymphocytes , Nippostrongylus , Animals , Mice , CD4-Positive T-Lymphocytes/immunology , Nippostrongylus/immunology , Strongylida Infections/immunology , Strongylida Infections/parasitology , Specific Pathogen-Free Organisms , Transcription, Genetic , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Helminthiasis/immunology , Interferon Type I/metabolism , Interferon Type I/immunology , Mice, Inbred C57BL , Lymphocyte Activation/immunologyABSTRACT
INTRODUCTION: Enfortumab vedotin is an antibody drug conjugate approved for management of pretreated locally advanced or metastatic urothelial carcinoma, which is associated with a rare risk of drug extravasation and soft tissue reactions. CASE REPORT: We report two cases of EV extravasation with subsequent development of bullae and cellulitis. MANAGEMENT AND OUTCOME: They were both treated for cellulitis and had conservative management without surgical intervention and were able to resume treatment with Enfortumab vedotin without subsequent adverse events. DISCUSSION: We propose that EV acts as a vesicant upon extravasation, highlight measures to prevent extravasation events, and encourage appropriate measures when dealing such as attempt of aspiration, removal of catheter, application of compresses, and thorough documentation with photographic evidence.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Carcinoma, Transitional Cell/drug therapy , Urinary Bladder Neoplasms/drug therapy , Cellulitis/chemically induced , Antibodies, Monoclonal/adverse effectsSubject(s)
Interleukin-33 , Agammaglobulinaemia Tyrosine Kinase , Humans , Inflammation , MacrophagesABSTRACT
Type 2 immunity encompasses the mechanisms through which the immune system responds to helminths and an array of environmental substances such as allergens. In the developing world, billions of individuals are chronically infected with endemic parasitic helminths. In comparison, in the industrialized world, millions of individuals suffer from dysregulated type 2 immunity, referred to clinically as atopic diseases including asthma, allergic rhinitis, and atopic dermatitis. Thus, type 2 immunity must be carefully regulated to mount protective host responses yet avoid inappropriate activation and immunopathology. In this review, we describe the key players and connections at play in type 2 responses and focus on the emerging mechanisms involved in the negative regulation of type 2 immunity.
Subject(s)
Helminthiasis/immunology , Hypersensitivity, Immediate/immunology , Th2 Cells/immunology , Allergens/immunology , Animals , Helminths/immunology , Homeostasis , Humans , Immunosuppression Therapy , Th1-Th2 BalanceABSTRACT
Host responses against metazoan parasites or an array of environmental substances elicit type 2 immunity. Despite its protective function, type 2 immunity also drives allergic diseases. The mechanisms that regulate the magnitude of the type 2 response remain largely unknown. Here, we show that genetic ablation of a receptor tyrosine kinase encoded byTyro3in mice or the functional neutralization of its ortholog in human dendritic cells resulted in enhanced type 2 immunity. Furthermore, the TYRO3 agonist PROS1 was induced in T cells by the quintessential type 2 cytokine, interleukin-4. T cell-specificPros1knockouts phenocopied the loss ofTyro3 Thus, a PROS1-mediated feedback from adaptive immunity engages a rheostat, TYRO3, on innate immune cells to limit the intensity of type 2 responses.
Subject(s)
Adaptive Immunity/genetics , Asthma/immunology , Host-Parasite Interactions/immunology , Immunity, Innate/genetics , Receptor Protein-Tyrosine Kinases/physiology , Animals , Asthma/genetics , Blood Proteins/antagonists & inhibitors , Blood Proteins/genetics , Blood Proteins/metabolism , Dendritic Cells/immunology , Disease Models, Animal , Gene Knockout Techniques , Host-Parasite Interactions/genetics , Humans , Interleukin-4/immunology , Interleukin-4/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Nippostrongylus/immunology , Protein S , Pyroglyphidae/immunology , Receptor Protein-Tyrosine Kinases/genetics , Strongylida Infections/immunology , T-Lymphocytes/immunologyABSTRACT
MicroRNAs (miRNAs) are important regulators of cell fate decisions in immune responses. They act by coordinate repression of multiple target genes, a property that we exploited to uncover regulatory networks that govern T helper-2 (Th2) cells. A functional screen of individual miRNAs in primary T cells uncovered multiple miRNAs that inhibited Th2 cell differentiation. Among these were miR-24 and miR-27, miRNAs coexpressed from two genomic clusters, which each functioned independently to limit interleukin-4 (IL-4) production. Mice lacking both clusters in T cells displayed increased Th2 cell responses and tissue pathology in a mouse model of asthma. Gene expression and pathway analyses placed miR-27 upstream of genes known to regulate Th2 cells. They also identified targets not previously associated with Th2 cell biology which regulated IL-4 production in unbiased functional testing. Thus, elucidating the biological function and target repertoire of miR-24 and miR-27 reveals regulators of Th2 cell biology.
Subject(s)
Asthma/immunology , Interleukin-4/biosynthesis , MicroRNAs/genetics , Th2 Cells/immunology , Animals , Base Sequence , Cell Differentiation/genetics , Cell Differentiation/immunology , Cells, Cultured , Disease Models, Animal , Female , Inflammation/immunology , Interleukin-4/immunology , Lymphocyte Activation/immunology , Male , Mice , Mice, Knockout , Multigene Family/genetics , Sequence Analysis, RNA , Th2 Cells/cytologyABSTRACT
microRNAs (miRNA) are essential for regulatory T cell (Treg) function but little is known about the functional relevance of individual miRNA loci. We identified the miR-17-92 cluster as CD28 costimulation dependent, suggesting that it may be key for Treg development and function. Although overall immune homeostasis was maintained in mice with miR-17-92-deficient Tregs, expression of the miR-17-92 miRNA cluster was critical for Treg accumulation and function during an acute organ-specific autoimmune disease in vivo. Treg-specific loss of miR-17-92 expression resulted in exacerbated experimental autoimmune encephalitis and failure to establish clinical remission. Using peptide-MHC tetramers, we demonstrate that the miR-17-92 cluster was specifically required for the accumulation of activated Ag-specific Treg and for differentiation into IL-10-producing effector Treg.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/immunology , MicroRNAs/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Adult , Animals , Antigen Presentation , Apoptosis Regulatory Proteins/genetics , Bcl-2-Like Protein 11 , CD28 Antigens/immunology , Cells, Cultured , Costimulatory and Inhibitory T-Cell Receptors/immunology , Epitopes, T-Lymphocyte/immunology , Gene Deletion , Heterozygote , Histocompatibility Antigens Class II/immunology , Homeostasis , Humans , Interleukin-10/biosynthesis , Lymphocyte Activation , Male , Membrane Proteins/genetics , Mice , Mice, Knockout , MicroRNAs/genetics , Myelin-Oligodendrocyte Glycoprotein/immunology , PTEN Phosphohydrolase/deficiency , Peptide Fragments/immunology , Proto-Oncogene Proteins/genetics , RNA, Long Noncoding , Young AdultABSTRACT
Follicular helper T cells (TFH cells) are the prototypic helper T cell subset specialized to enable B cells to form germinal centers (GCs) and produce high-affinity antibodies. We found that expression of microRNAs (miRNAs) by T cells was essential for TFH cell differentiation. More specifically, we show that after immunization of mice with protein, the miRNA cluster miR-17â¼92 was critical for robust differentiation and function of TFH cells in a cell-intrinsic manner that occurred regardless of changes in proliferation. In a viral infection model, miR-17â¼92 restrained the expression of genes 'inappropriate' to the TFH cell subset, including the direct miR-17â¼92 target Rora. Removal of one Rora allele partially 'rescued' the inappropriate gene signature in miR-17â¼92-deficient TFH cells. Our results identify the miR-17â¼92 cluster as a critical regulator of T cell-dependent antibody responses, TFH cell differentiation and the fidelity of the TFH cell gene-expression program.
Subject(s)
Cell Differentiation/immunology , Gene Expression Regulation/immunology , MicroRNAs/immunology , Nuclear Receptor Subfamily 1, Group F, Member 1/immunology , T-Lymphocytes, Helper-Inducer/immunology , Adaptive Immunity/immunology , Animals , Arenaviridae Infections/immunology , Arenaviridae Infections/virology , Flow Cytometry , Immunohistochemistry , Lymphocytic choriomeningitis virus/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Nuclear Receptor Subfamily 1, Group F, Member 1/genetics , Statistics, Nonparametric , T-Lymphocytes, Helper-Inducer/cytologyABSTRACT
MicroRNAs (miRNAs) are crucial for regulatory T cell (Treg) stability and function. We report that microRNA-10a (miR-10a) is expressed in Tregs but not in other T cells including individual thymocyte subsets. Expression profiling in inbred mouse strains demonstrated that non-obese diabetic (NOD) mice with a genetic susceptibility for autoimmune diabetes have lower Treg-specific miR-10a expression than C57BL/6J autoimmune resistant mice. Inhibition of miR-10a expression in vitro leads to reduced FoxP3 expression levels and miR-10a expression is lower in unstable "exFoxP3" T cells. Unstable in vitro TGF-ß-induced, iTregs do not express miR-10a unless cultured in the presence of retinoic acid (RA) which has been associated with increased stability of iTreg, suggesting that miR-10a might play a role in stabilizing Treg. However, genetic ablation of miR-10a neither affected the number and phenotype of natural Treg nor the capacity of conventional T cells to induce FoxP3 in response to TGFß, RA, or a combination of the two. Thus, miR-10a is selectively expressed in Treg but inhibition by antagomiRs or genetic ablation resulted in discordant effects on FoxP3.