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PEGylated PLGA Nanoparticle Delivery of Eggmanone for T Cell Modulation: Applications in Rheumatic Autoimmunity.
Haycook CP, Balsamo JA, Glass EB, Williams CH, Hong CC, Major AS, Giorgio TD
(2020) Int J Nanomedicine 15: 1215-1228
MeSH Terms: Animals, Autoimmunity, CD4-Positive T-Lymphocytes, Cytokines, Drug Delivery Systems, Female, Hedgehog Proteins, Immunoglobulin Fragments, Immunologic Factors, Mice, Inbred C57BL, Nanoparticles, Polylactic Acid-Polyglycolic Acid Copolymer, Pyrimidinones, Rheumatic Diseases, T-Lymphocytes, T-Lymphocytes, Helper-Inducer, Thiophenes
Show Abstract · Added March 30, 2020
Background - Helper T cell activity is dysregulated in a number of diseases including those associated with rheumatic autoimmunity. Treatment options are limited and usually consist of systemic immune suppression, resulting in undesirable consequences from compromised immunity. Hedgehog (Hh) signaling has been implicated in the activation of T cells and the formation of the immune synapse, but remains understudied in the context of autoimmunity. Modulation of Hh signaling has the potential to enable controlled immunosuppression but a potential therapy has not yet been developed to leverage this opportunity.
Methods - In this work, we developed biodegradable nanoparticles to enable targeted delivery of eggmanone (Egm), a specific Hh inhibitor, to CD4 T cell subsets. We utilized two FDA-approved polymers, poly(lactic-co-glycolic acid) and polyethylene glycol, to generate hydrolytically degradable nanoparticles. Furthermore, we employed maleimide-thiol mediated conjugation chemistry to decorate nanoparticles with anti-CD4 F(ab') antibody fragments to enable targeted delivery of Egm.
Results - Our novel delivery system achieved a highly specific association with the majority of CD4 T cells present among a complex cell population. Additionally, we have demonstrated antigen-specific inhibition of CD4 T cell responses mediated by nanoparticle-formulated Egm.
Conclusion - This work is the first characterization of Egm's immunomodulatory potential. Importantly, this study also suggests the potential benefit of a biodegradable delivery vehicle that is rationally designed for preferential interaction with a specific immune cell subtype for targeted modulation of Hh signaling.
© 2020 Haycook et al.
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17 MeSH Terms
Osteopontin and iCD8α Cells Promote Intestinal Intraepithelial Lymphocyte Homeostasis.
Nazmi A, Greer MJ, Hoek KL, Piazuelo MB, Weitkamp JH, Olivares-Villagómez D
(2020) J Immunol 204: 1968-1981
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Epithelium, Female, Homeostasis, Humans, Hyaluronan Receptors, Intestines, Intraepithelial Lymphocytes, Killer Cells, Natural, Male, Mice, Mice, Inbred C57BL, Osteopontin, Receptors, Antigen, T-Cell, gamma-delta, Th17 Cells
Show Abstract · Added February 28, 2020
Intestinal intraepithelial lymphocytes (IEL) comprise a diverse population of cells residing in the epithelium at the interface between the intestinal lumen and the sterile environment of the lamina propria. Because of this anatomical location, IEL are considered critical components of intestinal immune responses. Indeed, IEL are involved in many different immunological processes, ranging from pathogen control to tissue stability. However, despite their critical importance in mucosal immune responses, very little is known about the homeostasis of different IEL subpopulations. The phosphoprotein osteopontin is important for critical physiological processes, including cellular immune responses, such as survival of Th17 cells and homeostasis of NK cells among others. Because of its impact in the immune system, we investigated the role of osteopontin in the homeostasis of IEL. In this study, we report that mice deficient in the expression of osteopontin exhibit reduced numbers of the IEL subpopulations TCRγδ, TCRβCD4, TCRβCD4CD8α, and TCRβCD8αα cells in comparison with wild-type mice. For some IEL subpopulations, the decrease in cell numbers could be attributed to apoptosis and reduced cell division. Moreover, we show in vitro that exogenous osteopontin stimulates the survival of murine IEL subpopulations and unfractionated IEL derived from human intestines, an effect mediated by CD44, a known osteopontin receptor. We also show that iCD8α IEL but not TCRγδ IEL, TCRβ IEL, or intestinal epithelial cells, can promote survival of different IEL populations via osteopontin, indicating an important role for iCD8α cells in the homeostasis of IEL.
Copyright © 2020 by The American Association of Immunologists, Inc.
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17 MeSH Terms
CD8 T cells regulate liver injury in obesity-related nonalcoholic fatty liver disease.
Breuer DA, Pacheco MC, Washington MK, Montgomery SA, Hasty AH, Kennedy AJ
(2020) Am J Physiol Gastrointest Liver Physiol 318: G211-G224
MeSH Terms: Animals, CD8-Positive T-Lymphocytes, Hepatic Stellate Cells, Hepatitis, Humans, Hyperlipidemias, Interleukin-10, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Non-alcoholic Fatty Liver Disease, Obesity, Receptors, LDL
Show Abstract · Added March 3, 2020
Nonalcoholic steatohepatitis (NASH) has increased in Western countries due to the prevalence of obesity. Current interests are aimed at identifying the type and function of immune cells that infiltrate the liver and key factors responsible for mediating their recruitment and activation in NASH. We investigated the function and phenotype of CD8 T cells under obese and nonobese NASH conditions. We found an elevation in CD8 staining in livers from obese human subjects with NASH and cirrhosis that positively correlated with α-smooth muscle actin, a marker of hepatic stellate cell (HSC) activation. CD8 T cells were elevated 3.5-fold in the livers of obese and hyperlipidemic NASH mice compared with obese hepatic steatosis mice. Isolated hepatic CD8 T cells from these mice expressed a cytotoxic IL-10-expressing phenotype, and depletion of CD8 T cells led to significant reductions in hepatic inflammation, HSC activation, and macrophage accumulation. Furthermore, hepatic CD8 T cells from obese and hyperlipidemic NASH mice activated HSCs in vitro and in vivo. Interestingly, in the lean NASH mouse model, depletion and knockdown of CD8 T cells did not impact liver inflammation or HSC activation. We demonstrated that under obese/hyperlipidemia conditions, CD8 T cell are key regulators of the progression of NASH, while under nonobese conditions they play a minimal role in driving the disease. Thus, therapies targeting CD8 T cells may be a novel approach for treatment of obesity-associated NASH. Our study demonstrates that CD8 T cells are the primary hepatic T cell population, are elevated in obese models of NASH, and directly activate hepatic stellate cells. In contrast, we find CD8 T cells from lean NASH models do not regulate NASH-associated inflammation or stellate cell activation. Thus, for the first time to our knowledge, we demonstrate that hepatic CD8 T cells are key players in obesity-associated NASH.
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15 MeSH Terms
Single-cell transcriptomics reveal polyclonal memory T-cell responses in skin with positive abacavir patch test results.
Redwood AJ, Rwandamuriye F, Chopra A, Leary S, Ram R, McDonnell W, Konvinse K, White K, Pavlos R, Koelle DM, Mallal S, Phillips EJ
(2019) J Allergy Clin Immunol 144: 1413-1416.e7
MeSH Terms: Aged, Anti-HIV Agents, Arthralgia, CD8-Positive T-Lymphocytes, Dideoxynucleosides, Drug Hypersensitivity, Drug-Related Side Effects and Adverse Reactions, Gene Expression Profiling, HLA-B Antigens, Headache, Humans, Immunologic Memory, Lymphocyte Activation, Male, Myalgia, Patch Tests, Single-Cell Analysis, Skin
Added March 30, 2020
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18 MeSH Terms
Prostaglandin regulation of T cell biology.
Maseda D, Ricciotti E, Crofford LJ
(2019) Pharmacol Res 149: 104456
MeSH Terms: Animals, Autoimmune Diseases, Cell Differentiation, Drug Discovery, Humans, Immunity, Inflammation, Prostaglandins, T-Lymphocytes
Show Abstract · Added March 25, 2020
Prostaglandins (PG) are pleiotropic bioactive lipids involved in the control of many physiological processes, including key roles in regulating inflammation. This links PG to the modulation of the quality and magnitude of immune responses. T cells, as a core part of the immune system, respond readily to inflammatory cues from their environment, and express a diverse array of PG receptors that contribute to their function and phenotype. Here we put in context our knowledge about how PG affect T cell biology, and review advances that bring light into how specific T cell functions that have been newly discovered are modulated through PG. We will also comment on drugs that target PG metabolism and sensing, their effect on T cell function during disease, and we will finally discuss how we can design new approaches that modulate PG in order to maximize desired therapeutic T cell effects.
Published by Elsevier Ltd.
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9 MeSH Terms
Immune-mediated adverse reactions to vaccines.
Stone CA, Rukasin CRF, Beachkofsky TM, Phillips EJ
(2019) Br J Clin Pharmacol 85: 2694-2706
MeSH Terms: Guillain-Barre Syndrome, Humans, Hypersensitivity, Delayed, Hypersensitivity, Immediate, Immunocompromised Host, Immunoglobulin E, Skin Tests, T-Lymphocytes, Vaccination, Vaccine Excipients, Vaccines
Show Abstract · Added March 30, 2020
Vaccination continues to be the single most important and successful public health intervention, due to its prevention of morbidity and mortality from prevalent infectious diseases. Severe immunologically mediated reactions are rare and less common with the vaccine than the true infection. However, these events can cause public fearfulness and loss of confidence in the safety of vaccination. In this paper, we perform a systematic literature search and narrative review of immune-mediated vaccine adverse events and their known and proposed mechanisms, and outline directions for future research. Improving our knowledge base of severe immunologically mediated vaccine reactions and their management drives better vaccine safety and efficacy outcomes.
© 2019 The British Pharmacological Society.
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11 MeSH Terms
Editorial: Role of CD1- and MR1-Restricted T Cells in Immunity and Disease.
Iwabuchi K, Van Kaer L
(2019) Front Immunol 10: 1837
MeSH Terms: Animals, Antigens, CD1, Histocompatibility Antigens Class I, Humans, Minor Histocompatibility Antigens, Mucosal-Associated Invariant T Cells, Natural Killer T-Cells, Receptors, Antigen, T-Cell, T-Lymphocytes
Added March 3, 2020
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9 MeSH Terms
Identification of drug-specific public TCR driving severe cutaneous adverse reactions.
Pan RY, Chu MT, Wang CW, Lee YS, Lemonnier F, Michels AW, Schutte R, Ostrov DA, Chen CB, Phillips EJ, Mallal SA, Mockenhaupt M, Bellón T, Tassaneeyakul W, White KD, Roujeau JC, Chung WH, Hung SI
(2019) Nat Commun 10: 3569
MeSH Terms: Adoptive Transfer, Adult, Aged, Animals, Carbamazepine, Disease Models, Animal, Female, HLA-B15 Antigen, Humans, Male, Mice, Transgenic, Middle Aged, Receptor-CD3 Complex, Antigen, T-Cell, Receptors, Antigen, T-Cell, alpha-beta, Severity of Illness Index, Skin, Stevens-Johnson Syndrome, T-Lymphocytes, Cytotoxic
Show Abstract · Added March 30, 2020
Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αβTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype-specificity and an bias for HLA-B*15:02. This public αβTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αβTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.
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Characterization of Magnitude and Antigen Specificity of HLA-DP, DQ, and DRB3/4/5 Restricted DENV-Specific CD4+ T Cell Responses.
Grifoni A, Moore E, Voic H, Sidney J, Phillips E, Jadi R, Mallal S, De Silva AD, De Silva AM, Peters B, Weiskopf D, Sette A
(2019) Front Immunol 10: 1568
MeSH Terms: Alleles, Antibody Specificity, CD4-Positive T-Lymphocytes, Dengue, Dengue Virus, Epitopes, T-Lymphocyte, HLA-DP Antigens, HLA-DRB1 Chains, Humans, Interferon-gamma
Show Abstract · Added March 30, 2020
Dengue Virus (DENV) associated disease is a major public health problem. Assessment of HLA class II restricted DENV-specific responses is relevant for immunopathology and definition of correlates of protection. While previous studies characterized responses restricted by the HLA-DRB1 locus, the responses associated with other class II loci have not been characterized to date. Accordingly, we mapped HLA-DP, DQ, and DRB3/4/5 restricted DENV-specific CD4 T cell epitopes in PBMCs derived from the DENV endemic region Sri Lanka. We studied 12 DP, DQ, and DRB3/4/5 alleles that are commonly expressed and provide worldwide coverage >82% for each of the loci analyzed and >99% when combined. CD4+ T cells purified by negative selection were stimulated with pools of HLA-predicted binders for 2 weeks with autologous APC. Epitope reactive T cells were enumerated using IFNγ ELISPOT assay. This strategy was previously applied to identify DRB1 restricted epitopes. In parallel, membrane expression levels of HLA-DR, DP, and DQ proteins was assessed using flow cytometry. Epitopes were identified for all DP, DQ, and DRB3/4/5 allelic variants albeit with magnitudes significantly lower than the ones previously observed for the DRB1 locus. This was in line with lower membrane expression of HLA-DP and DQ molecules on the PBMCs tested, as compared to HLA-DR. Significant differences between loci were observed in antigen immunodominance. Capsid responses were dominant for DRB1/3/4/5 and DP alleles but negligible for the DQ alleles. NS3 responses were dominant in the case of DRB1/3/4/5 and DQ but absent in the case of DP. NS1 responses were prominent in the case of the DP alleles, but negligible in the case of DR and DQ. In terms of epitope specificity, repertoire was largely overlapping between DRB1 and DRB3/4/5, while DP and DQ loci recognized largely distinct epitope sets. The HLA-DP, DQ, and DRB3/4/5 loci mediate DENV-CD4 specific immune responses of lower magnitude as compared to HLA-DRB1, consistent with their lower levels of expression. The responses are associated with distinct and characteristic patterns of immunodominance, and variable epitope overlap across loci.
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10 MeSH Terms
A case report of clonal EBV-like memory CD4 T cell activation in fatal checkpoint inhibitor-induced encephalitis.
Johnson DB, McDonnell WJ, Gonzalez-Ericsson PI, Al-Rohil RN, Mobley BC, Salem JE, Wang DY, Sanchez V, Wang Y, Chastain CA, Barker K, Liang Y, Warren S, Beechem JM, Menzies AM, Tio M, Long GV, Cohen JV, Guidon AC, O'Hare M, Chandra S, Chowdhary A, Lebrun-Vignes B, Goldinger SM, Rushing EJ, Buchbinder EI, Mallal SA, Shi C, Xu Y, Moslehi JJ, Sanders ME, Sosman JA, Balko JM
(2019) Nat Med 25: 1243-1250
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, CD4-Positive T-Lymphocytes, Encephalitis, Female, Herpesvirus 4, Human, Humans, Immunologic Memory, Lymphocyte Activation, Male, Middle Aged, Programmed Cell Death 1 Receptor, Young Adult
Show Abstract · Added November 12, 2019
Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4 T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45ROGZMBKi67) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4 and CD8 T cells as culprits of checkpoint inhibitor-associated immune encephalitis.
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