scholarly journals Interferon-gamma (IFN-γ): Exploring its implications in infectious diseases

2018 ◽  
Vol 9 (1) ◽  
pp. 64-79 ◽  
Author(s):  
Gunjan Kak ◽  
Mohsin Raza ◽  
Brijendra K Tiwari
Keyword(s):  
Infectious Diseases ◽  
Antigen Processing ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Cell Activity ◽  
Type I ◽  
Altered Expression ◽  
Ifn Γ

AbstractA key player in driving cellular immunity, IFN-γ is capable of orchestrating numerous protective functions to heighten immune responses in infections and cancers. It can exhibit its immunomodulatory effects by enhancing antigen processing and presentation, increasing leukocyte trafficking, inducing an anti-viral state, boosting the anti-microbial functions and affecting cellular proliferation and apoptosis. A complex interplay between immune cell activity and IFN-γ through coordinated integration of signals from other pathways involving cytokines and Pattern Recognition Receptors (PRRs) such as Interleukin (IL)-4, TNF-α, Lipopolysaccharide (LPS), Type-I Interferons (IFNS) etc. leads to initiation of a cascade of pro-inflammatory responses. Microarray data has unraveled numerous genes whose transcriptional regulation is influenced by IFN-γ. Consequently, IFN-γ stimulated cells display altered expression of many such target genes which mediate its downstream effector functions. The importance of IFN-γ is further reinforced by the fact that mice possessing disruptions in the IFN-γ gene or its receptor develop extreme susceptibility to infectious diseases and rapidly succumb to them. In this review, we attempt to elucidate the biological functions and physiological importance of this versatile cytokine. The functional implications of its biological activity in several infectious diseases and autoimmune pathologies are also discussed. As a counter strategy, many virulent pathogenic species have devised ways to thwart IFN-γ endowed immune-protection. Thus, IFN-γ mediated host-pathogen interactions are critical for our understanding of disease mechanisms and these aspects also manifest enormous therapeutic importance for the annulment of various infections and autoimmune conditions.

Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer’s Disease

2021 ◽  
pp. 1-16
Author(s):  
Staley A. Brod
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Cognitive Decline ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Type I ◽  
Type I Ifn ◽  
Anti Inflammatory

Systemic inflammation is an organism’s response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer’s disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the “principal culprit” in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1 : 1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD.

scholarly journals DOP17 Identification of biomarkers and mechanistic insight for upadacitinib in ulcerative colitis: Analysis of serum inflammatory mediators in the phase 2b U-ACHIEVE study

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S057-S058
Author(s):  
S Vermeire ◽  
H Guay ◽  
B Verstockt ◽  
J Fann ◽  
J Cheng ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Dendritic Cell ◽  
Inflammatory Mediators ◽  
Immune Cell ◽  
Cell Activity ◽  
Type I ◽  
Serum Samples ◽  
Cell Responses ◽  
Immune Cell Migration ◽  
Migration Type

Abstract Background The U-ACHIEVE trial evaluated upadacitinib (UPA), an oral JAK1 selective inhibitor, in patients with moderately to severely active ulcerative colitis (UC). Patient-reported and endoscopic outcomes improved after UPA treatment. This analysis used pharmacodynamic profiling to link changes in serum biomarkers to changes in UC disease activity, and to assess the UPA mechanism of action in UC. Methods U-ACHIEVE (NCT02819635) was a randomised, double-blind, placebo (PBO)-controlled phase 2b clinical trial. Adults with an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, or biologic therapies were randomised to receive 7.5, 15, 30, or 45 mg UPA once daily or PBO for 8 weeks (weeks). Serum samples (baseline [BL], weeks 2, 4, and 8) were analysed by OLINK® inflammation panel (92 proteins) and by Singulex immunoassay for interleukin-1b (IL-1b), IL-17A, IL-17F, and IL-22. Protein-level changes were analysed by a mixed-effect model; BL protein level was adjusted as a covariate; treatment group, time point, and their interaction were included as fixed effects. Spearman rank-correlation coefficients were used to determine the relationship between changes of serum biomarker levels and improvements in adapted Mayo scores and endoscopic subscores. Multiplicity adjusted P values were calculated using 1000 runs of random permutations. Results Paired BL and week 8 serum samples were available from 114 patients (PBO, n = 17; UPA 7.5 mg, n = 21; UPA 15 mg, n = 21; UPA 30 mg, n = 29; UPA 45 mg, n = 26). UPA treatment reduced expression of pro-inflammatory mediators associated with immune cell migration, type I/II IFN responses, T-cell responses, macrophage and dendritic cell activity and increased expression of biomarkers associated with haematopoiesis, neuroprotection and mucosal repair in a dose-dependent manner. Improvements in adapted Mayo score, endoscopic subscore, and stool frequency correlated with increases in CX3CL1, DNER and FLt3L (p < 0.05 for all). Endoscopic improvements correlated with reductions in OSM, and improvements in fatigue correlated with increases in CCL25 and NT-3. There was a substantial overlap in biomarkers modulated by UPA in patients with UC and Crohn’s disease (Figure). Conclusion UPA modulated expression of serum pro-inflammatory mediators found in pathways associated with the pathogenesis of UC, including immune cell migration, type I/II IFN responses, T-cell responses, macrophage and dendritic cell activity, haematopoiesis, neuroprotection, and mucosal repair. Consistent correlations were observed between changes in biomarker expression and improvements in disease activity and symptoms of UC.

scholarly journals Modulation of monocyte responses by progressive multiple sclerosis therapy.

2021 ◽  
Author(s):  
◽  
Carl Beyers
Keyword(s):  
Multiple Sclerosis ◽  
Inflammatory Cytokines ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Neurodegenerative Disorder ◽  
Cell Activity ◽  
Cell Subset ◽  
Disease Heterogeneity ◽  
Receptor Affinity ◽  
Anti Inflammatory

<p>Multiple sclerosis (MS) is an immune-mediated neurodegenerative disorder that is distinguished by neuroinflammation and demyelination. MS is severely debilitating and remains the most common cause of disability arising from non-traumatic brain and CNS damage in adults. In its progressive phase there are no effective treatments, so new therapy options are an urgent research priority. Extensive work has been done on the role of the adaptive immune system in contributing to the disease pathology and on the effects of therapies targeting lymphocytes in relapsing-remitting MS. Fewer studies have examined innate immune cells in people with progressive MS. This thesis addresses that gap by profiling monocyte phenotype and function in response to new and repurposed drugs that may provide benefit in progressive MS. This was achieved by modelling the drugs’ effects in vitro using peripheral blood cells from people with progressive MS and healthy subjects.   Clozapine is an atypical antipsychotic with broad receptor affinity that is primarily used to treat refractory schizophrenia. In addition to is antipsychotic action through dopamine receptor (DR) D2, its broad neuro-immune receptor affinity is thought to dampen inflammatory responses in the CNS. This thesis highlights clozapine’s anti-inflammatory effect by demonstrating a reduction in the expression of pro-inflammatory cytokines that are associated with MS pathology in treated monocytes. Clozapine also induced a significant increase in the expression of D1. We observed that D1 expression changes happened alongside alterations to immune cell activity and that MS participant monocytes were much more susceptible to DR expression changes compared to healthy people. Together this data substantiates clozapine as a potential treatment for progressive disease.   MIS416 is a large, non-soluble microparticle suspension that induces nuclear factor kappa B (NFB) dependent cytokine induction. We show here that monocytes are key cytokine responder cells to MIS416 and explore the molecular mechanism by demonstrating its effects on transcription factor activity. Our data showing increased production of cytokines by MIS416 suggests a route of treatment efficacy through tolerisation mechanisms, and by reducing inflammation through upregulation of anti-inflammatory cytokines and negative feedback from pro-inflammatory cytokine release. Furthermore, we demonstrate how disease heterogeneity, phenotype, and genotype could significantly affect drug response outcomes in patients who received the drug as part of a phase 2 clinical trial.   Much of this work was done using new spectral cytometer technology. Its use allowed for the novel approach that enabled the subtraction of autofluorescent noise from out data, and we demonstrate its efficient functioning, ease of use, and utility in acquiring high dimensional datasets. The resulting large dataset allowed us the opportunity to interrogate it using bioinformatics tools, and we show their utility as adjunct tools to conventional methods of gating and statistical analysis. These analyses help demonstrate that monocytes are a heterogenous immune cell subset that is functionally distinct in people with progressive MS when compared to monocytes from healthy individuals.</p>

scholarly journals A Novel Interferon Regulatory Factor (IRF), IRF-10, Has a Unique Role in Immune Defense and Is Induced by the v-Rel Oncoprotein

2002 ◽  
Vol 22 (11) ◽  
pp. 3942-3957 ◽  
Author(s):  
Jiří Nehyba ◽  
Radmila Hrdličková ◽  
Joan Burnside ◽  
Henry R. Bose
Keyword(s):  
Mhc Class I ◽  
Target Genes ◽  
Interferon Regulatory Factor ◽  
Inducible Expression ◽  
Immune Defense ◽  
Class I ◽  
Type I ◽  
Regulatory Factor ◽  
Unique Role ◽  
Ifn Γ

ABSTRACT The cloning and functional characterization of a novel interferon regulatory factor (IRF), IRF-10, are described. IRF-10 is most closely related to IRF-4 but differs in both its constitutive and inducible expression. The expression of IRF-10 is inducible by interferons (IFNs) and by concanavalin A. In contrast to that of other IRFs, the inducible expression of IRF-10 is characterized by delayed kinetics and requires protein synthesis, suggesting a unique role in the later stages of an antiviral defense. Accordingly, IRF-10 is involved in the upregulation of two primary IFN-γ target genes (major histocompatibility complex [MHC] class I and guanylate-binding protein) and interferes with the induction of the type I IFN target gene for 2′,5′-oligo(A) synthetase. IRF-10 binds the interferon-stimulated response element site of the MHC class I promoter. In contrast to that of IRF-1, which has some of the same functional characteristics, the expression of IRF-10 is not cytotoxic for fibroblasts or B cells. The expression of IRF-10 is induced by the oncogene v-rel, the proto-oncogene c-rel, and IRF-4 in a tissue-specific manner. Moreover, v-Rel and IRF-4 synergistically cooperate in the induction of IRF-10 in fibroblasts. The level of IRF-10 induction in lymphoid cell lines by Rel proteins correlates with Rel transformation potential. These results suggest that IRF-10 plays a role in the late stages of an immune defense by regulating the expression some of the IFN-γ target genes in the absence of a cytotoxic effect. Furthermore, IRF-10 expression is regulated, at least in part, by members of the Rel/NF-κB and IRF families.

IFNg-Mediated MHC-II Expression in Mesenchymal Stem Cells (MSC) Is Concentration-Dependent.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4250-4250
Author(s):  
Katherine C. Tang ◽  
Sergei Kotenko ◽  
Jonathan S. Harrison ◽  
Pranela Rameshwar
Keyword(s):  
Stem Cells ◽  
Tissue Repair ◽  
Adult Stem Cell ◽  
Suppressor Cells ◽  
Type I ◽  
Western Blots ◽  
Altered Expression ◽  
Mhc Ii ◽  
Ifn Γ ◽  
Low Efficiency

Abstract A significant concern in tissue repair is allo-rejection in a host with MHC-II mismatch. Since MSC appear to have veto properties to offset its own rejection, these stem cells may serve as ideal candidates in repair medicine. Interferon-g (IFN-g), which exacerbates immune responses, is known to enhance the expression of MHC-II in antigen presenting cells (e.g., macrophages). This led to the question on the mechanism by which MSC act as immune suppressor cells. We hypothesize that endogenous IFN-γ maintains basal MHC-II expression, while increased levels lead to its down regulation. Indeed, we observed a biphasic response of IFN-γ on the expression of MHC-II. While unstimulated MSC produced 19±5 pg/ml IFN-γ, exogenous IFN-γ (&gt;100 U/ml) led to decreased expression of MHC-II. Suppression of IFN-g by siRNA resulted in undetectable MHC-II. The response of exogenous IFN-γ could not be explained by altered expression of IFN-g receptor type I (IFN-γRI) or changes in STAT-1 activation. However, western blots showed multiple isotypes of the MHC-II master regulator transcription factor, CIITA, in IFN-γ-stimulated MSC, with predominance of CIITA exhibiting low efficiency binding to DNA. This observation might explain why MHC-II is undetectable in the presence of high levels of IFN-γ. These findings support a potential for MSC as an adult stem cell in tissue repair.

scholarly journals Modulation of monocyte responses by progressive multiple sclerosis therapy.

2021 ◽  
Author(s):  
◽  
Carl Beyers
Keyword(s):  
Multiple Sclerosis ◽  
Inflammatory Cytokines ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Neurodegenerative Disorder ◽  
Cell Activity ◽  
Cell Subset ◽  
Disease Heterogeneity ◽  
Receptor Affinity ◽  
Anti Inflammatory

<p>Multiple sclerosis (MS) is an immune-mediated neurodegenerative disorder that is distinguished by neuroinflammation and demyelination. MS is severely debilitating and remains the most common cause of disability arising from non-traumatic brain and CNS damage in adults. In its progressive phase there are no effective treatments, so new therapy options are an urgent research priority. Extensive work has been done on the role of the adaptive immune system in contributing to the disease pathology and on the effects of therapies targeting lymphocytes in relapsing-remitting MS. Fewer studies have examined innate immune cells in people with progressive MS. This thesis addresses that gap by profiling monocyte phenotype and function in response to new and repurposed drugs that may provide benefit in progressive MS. This was achieved by modelling the drugs’ effects in vitro using peripheral blood cells from people with progressive MS and healthy subjects.   Clozapine is an atypical antipsychotic with broad receptor affinity that is primarily used to treat refractory schizophrenia. In addition to is antipsychotic action through dopamine receptor (DR) D2, its broad neuro-immune receptor affinity is thought to dampen inflammatory responses in the CNS. This thesis highlights clozapine’s anti-inflammatory effect by demonstrating a reduction in the expression of pro-inflammatory cytokines that are associated with MS pathology in treated monocytes. Clozapine also induced a significant increase in the expression of D1. We observed that D1 expression changes happened alongside alterations to immune cell activity and that MS participant monocytes were much more susceptible to DR expression changes compared to healthy people. Together this data substantiates clozapine as a potential treatment for progressive disease.   MIS416 is a large, non-soluble microparticle suspension that induces nuclear factor kappa B (NFB) dependent cytokine induction. We show here that monocytes are key cytokine responder cells to MIS416 and explore the molecular mechanism by demonstrating its effects on transcription factor activity. Our data showing increased production of cytokines by MIS416 suggests a route of treatment efficacy through tolerisation mechanisms, and by reducing inflammation through upregulation of anti-inflammatory cytokines and negative feedback from pro-inflammatory cytokine release. Furthermore, we demonstrate how disease heterogeneity, phenotype, and genotype could significantly affect drug response outcomes in patients who received the drug as part of a phase 2 clinical trial.   Much of this work was done using new spectral cytometer technology. Its use allowed for the novel approach that enabled the subtraction of autofluorescent noise from out data, and we demonstrate its efficient functioning, ease of use, and utility in acquiring high dimensional datasets. The resulting large dataset allowed us the opportunity to interrogate it using bioinformatics tools, and we show their utility as adjunct tools to conventional methods of gating and statistical analysis. These analyses help demonstrate that monocytes are a heterogenous immune cell subset that is functionally distinct in people with progressive MS when compared to monocytes from healthy individuals.</p>

scholarly journals Computational Analysis Revealed miRNAs Produced by Chikungunya Virus Target Genes Associated with Cellular Proliferation and Cell Cycle Regulation

2020 ◽  
Author(s):  
Md. Sajedul Islam ◽  
Md. Abdullah-Al-Kamran Khan
Keyword(s):  
Cell Cycle ◽  
Chikungunya Virus ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Enrichment Analysis ◽  
Microarray Dataset ◽  
Functional Enrichment ◽  
P Value ◽  
Altered Expression ◽  
Regulatory Pathways

Abstract Chikungunya virus (CHIKV) that causes chikungunya fever, is an alphavirus that belongs to the Togaviridae family containing a single-stranded RNA genome. Mosquitoes of the Aedes species act as the vectors for this virus and can be found in the blood, which can be passed from an infected person to a mosquito through mosquito bites. CHIKV has drawn much attention recently because of its potential of causing an epidemic. As the detailed mechanism of its pathogenesis inside the host system is still lacking, in this in silico research we have hypothesized that CHIKV might create miRNAs, which would target the genes associated with host cellular regulatory pathways, thereby providing the virus with prolonged refuge. Using bioinformatics approaches we found several putative miRNAs produced by CHIKV. Then we predicted the genes of the host targeted by these miRNAs. Functional enrichment analysis of these targeted genes shows the involvement of several biological pathways regulating cellular proliferation and cell cycle, thereby provide themselves with prolonged refuge and facilitate their pathogenesis, which in turn may lead to disease conditions. Finally, we analyzed a publicly available microarray dataset (GSE49985) to determine the altered expression levels of the targeted genes and found four genes (FLNA, GATA6, HES6, and TP53) associated with transcription factor binding, which have significant (Adjusted p-value <0.05) altered expression level. Our finding presents novel miRNAs and their targeted genes, which upon experimental validation could facilitate in developing new therapeutics to combat CHIKV infection and minimize CHIKV mediated diseases.

scholarly journals IRGM3 Contributes to Immunopathology and Is Required for Differentiation of Antigen-Specific Effector CD8+T Cells in Experimental Cerebral Malaria

2015 ◽  
Vol 83 (4) ◽  
pp. 1406-1417 ◽  
Author(s):  
Jintao Guo ◽  
James A. McQuillan ◽  
Belinda Yau ◽  
Gregory S. Tullo ◽  
Carole A. Long ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Type I ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Cytokines And Chemokines ◽  
Specific Effector ◽  
Ifn Γ

Gamma interferon (IFN-γ) drives antiparasite responses and immunopathology during infection withPlasmodiumspecies. Immunity-related GTPases (IRGs) are a class of IFN-γ-dependent proteins that are essential for cell autonomous immunity to numerous intracellular pathogens. However, it is currently unknown whether IRGs modulate responses during malaria. We have used thePlasmodium bergheiANKA (PbA) model in which mice develop experimental cerebral malaria (ECM) to study the roles of IRGM1 and IRGM3 in immunopathology. Induction of mRNA forIrgm1andIrgm3was found in the brains and spleens of infected mice at times of peak IFN-γ production.Irgm3−/−but notIrgm1−/−mice were completely protected from the development of ECM, and this protection was associated with the decreased induction of inflammatory cytokines, as well as decreased recruitment and activation of CD8+T cells within the brain. Although antigen-specific proliferation of transferred CD8+T cells was not diminished compared to that of wild-type recipients following PbA infection, T cells transferred intoIrgm3−/−recipients showed a striking impairment of effector differentiation. Decreased induction of several inflammatory cytokines and chemokines (interleukin-6, CCL2, CCL3, and CCL4), as well as enhanced mRNA expression of type-I IFNs, was found in the spleens ofIrgm3−/−mice at day 4 postinfection. Together, these data suggest that protection from ECM pathology inIrgm3−/−mice occurs due to impaired generation of CD8+effector function. This defect is nonintrinsic to CD8+T cells. Instead, diminished T cell responses most likely result from defective initiation of inflammatory responses in myeloid cells.

scholarly journals Complement Has Brains—Do Intracellular Complement and Immunometabolism Cooperate in Tissue Homeostasis and Behavior?

2021 ◽  
Vol 12 ◽  
Author(s):  
Natalia Kunz ◽  
Claudia Kemper
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Complement System ◽  
Immune Cell ◽  
Cell Activity ◽  
Metabolic Reprogramming ◽  
Normal Brain ◽  
Peripheral Tissues ◽  
Ifn Γ ◽  
The Brain

The classical liver-derived and serum-effective complement system is well appreciated as a key mediator of host protection via instruction of innate and adaptive immunity. However, recent studies have discovered an intracellularly active complement system, the complosome, which has emerged as a central regulator of the core metabolic pathways fueling human immune cell activity. Induction of expression of components of the complosome, particularly complement component C3, during transmigration from the circulation into peripheral tissues is a defining characteristic of monocytes and T cells in tissues. Intracellular complement activity is required to induce metabolic reprogramming of immune cells, including increased glycolytic flux and OXPHOS, which drive the production of the pro-inflammatory cytokine IFN-γ. Consequently, reduced complosome activity translates into defects in normal monocyte activation, faulty Th1 and cytotoxic T lymphocyte responses and loss of protective tissue immunity. Intriguingly, neurological research has identified an unexpected connection between the physiological presence of innate and adaptive immune cells and certain cytokines, including IFN-γ, in and around the brain and normal brain function. In this opinion piece, we will first review the current state of research regarding complement driven metabolic reprogramming in the context of immune cell tissue entry and residency. We will then discuss how published work on the role of IFN-γ and T cells in the brain support a hypothesis that an evolutionarily conserved cooperation between the complosome, cell metabolism and IFN-γ regulates organismal behavior, as well as immunity.

scholarly journals An Integrated Genomic, Proteomic, and Immunopeptidomic Approach to Discover Treatment-Induced Neoantigens

2021 ◽  
Vol 12 ◽  
Author(s):  
Niclas Olsson ◽  
Marlene L. Heberling ◽  
Lichao Zhang ◽  
Suchit Jhunjhunwala ◽  
Qui T. Phung ◽  
...  
Keyword(s):  
Immune Responses ◽  
Antigen Presentation ◽  
Mammalian Cells ◽  
Antigen Processing ◽  
Immune Surveillance ◽  
Specific Antigen ◽  
Spectrometric Analysis ◽  
Altered Expression ◽  
Mhc Molecules ◽  
Ifn Γ

All nucleated mammalian cells express major histocompatibility complex (MHC) proteins that present peptides on cell surfaces for immune surveillance. These MHC-presented peptides (pMHC) are necessary for directing T-cell responses against cells harboring non-self antigens derived from pathogens or from somatic mutations. Alterations in tumor-specific antigen repertoires — particularly novel MHC presentation of mutation-bearing peptides (neoantigens) — can be potent targets of anti-tumor immune responses. Here we employed an integrated genomic and proteomic antigen discovery strategy aimed at measuring how interferon gamma (IFN-γ) alters antigen presentation, using a human lymphoma cell line, GRANTA-519. IFN-γ treatment resulted in 126 differentially expressed proteins (2% of all quantified proteins), which included components of antigen presentation machinery and interferon signaling pathways, and MHC molecules themselves. In addition, several proteasome subunits were found to be modulated, consistent with previous reports of immunoproteasome induction by IFN-γ exposure. This finding suggests that a modest proteomic response to IFN-γ could create larger alteration to cells’ antigen/epitope repertoires. Accordingly, MHC immunoprecipitation followed by mass spectrometric analysis of eluted peptide repertoires revealed exclusive signatures of IFN-γ induction, with 951 unique peptides reproducibly presented by MHC-I and 582 presented by MHC-II. Furthermore, an additional set of pMHCs including several candidate neoantigens, distinguished control and the IFN-γ samples by their altered relative abundances. Accordingly, we developed a classification system to distinguish peptides which are differentially presented due to altered expression from novel peptides resulting from changes in antigen processing. Taken together, these data demonstrate that IFN-γ can re-shape antigen repertoires by identity and by abundance. Extending this approach to models with greater clinical relevance could help develop strategies by which immunopeptide repertoires are intentionally reshaped to improve endogenous or vaccine-induced anti-tumor immune responses and potentially anti-viral immune responses.

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