ABSTRACT
Immune homeostasis in peripheral tissues is, to a large degree, maintained by the differentiation and action of regulatory T cells (Treg) specific for tissue Ags. Using a novel mouse model, we have studied the differentiation of naive CD4+ T cells into Foxp3+ Treg in response to a cutaneous Ag (OVA). We found that expression of OVA resulted in fatal autoimmunity and in prevention of peripheral Treg generation. Inhibiting mTOR activity with rapamycin rescued the generation of Foxp3+ T cells. When we varied the level of Ag expression to modulate TCR signaling, we found that low Ag concentrations promoted the generation of Foxp3+ T cells, whereas high levels expanded effector T cells and caused severe autoimmunity. Our findings indicate that the expression level of tissue Ag is a key determinant of the balance between tissue-reactive effector and peripheral Foxp3+ T cells, which determines the choice between tolerance and autoimmunity.
Subject(s)
Autoimmune Diseases/immunology , Cell Differentiation/immunology , Lymphocyte Activation , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Autoimmune Diseases/pathology , Disease Models, Animal , Forkhead Transcription Factors/metabolism , Humans , Mice , Mice, Transgenic , Ovalbumin/genetics , Ovalbumin/immunology , Receptors, Antigen, T-Cell/metabolism , Signal Transduction/drug effects , Signal Transduction/immunology , Sirolimus/pharmacology , Skin/immunology , Skin/pathology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolismABSTRACT
Genetic activation of hedgehog/glioma-associated oncogene homolog (HH/GLI) signaling causes basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer. Small molecule targeting of the essential HH effector Smoothened (SMO) has proven an effective therapy of BCC, though the frequent development of drug resistance poses major challenges to anti-HH treatments. In light of recent breakthroughs in cancer immunotherapy, we analyzed the possible immunosuppressive mechanisms in HH/GLI-induced BCC in detail. Using a genetic mouse model of BCC, we identified profound differences in the infiltration of BCC lesions with cells of the adaptive and innate immune system. Epidermal activation of Hh/Gli signaling led to an accumulation of immunosuppressive regulatory T cells, and to an increased expression of immune checkpoint molecules including programmed death (PD)-1/PD-ligand 1. Anti-PD-1 monotherapy, however, did not reduce tumor growth, presumably due to the lack of immunogenic mutations in common BCC mouse models, as shown by whole-exome sequencing. BCC lesions also displayed a marked infiltration with neutrophils, the depletion of which unexpectedly promoted BCC growth. The study provides a comprehensive survey of and novel insights into the immune status of murine BCC and serves as a basis for the design of efficacious rational combination treatments. This study also underlines the need for predictive immunogenic mouse models of BCC to evaluate the efficacy of immunotherapeutic strategies in vivo.
Subject(s)
Carcinoma, Basal Cell/immunology , Epidermis/pathology , Hedgehog Proteins/metabolism , Immunity , Immunosuppression Therapy , Signal Transduction , Skin Neoplasms/immunology , Tumor Microenvironment/immunology , Animals , Carcinoma, Basal Cell/pathology , Cell Proliferation , Chemokines/metabolism , Immune Checkpoint Proteins/metabolism , Mice , Neutrophils/metabolism , Oncogenes , Skin Neoplasms/pathology , T-Lymphocytes/immunology , Zinc Finger Protein GLI1/metabolismSubject(s)
Carrier Proteins/genetics , Depressive Disorder, Major/genetics , Membrane Glycoproteins/genetics , Membrane Transport Proteins , Nerve Tissue Proteins , Polymorphism, Genetic/genetics , Receptors, Serotonin/genetics , Suicide , Tryptophan Hydroxylase/genetics , Alleles , Brain , Genotype , Humans , Receptor, Serotonin, 5-HT2A , Serotonin Plasma Membrane Transport Proteins , Suicide/psychologyABSTRACT
Cyclodextrin (CD) polymer, a type of crosslinked cyclodextrin, has been evaluated as a new tablet disintegrating agent in comparison with four common disintegrants (crosslinked polyvinylpyrrolidone, crosslinked carboxymethyl cellulose, formaldehyde casein and corn starch). Physical properties of the disintegrants have been studied. Tablets made by direct compression using microcrystalline cellulose as binder, magnesium stearate as lubricant and talc as antiadherent have been compared. The parameters evaluated were disintegration time, hardness and friability. CD polymer performs well as a tablet disintegrating agent with results paralleling those of crosslinked carboxymethyl cellulose (Ac-Di-Sol) and superior to the other three.
