Major Histocompatibility Molecules Research Articles

The role of natural killer T cells in liver transplantation.

Natural killer T cells (NKTs) are innate-like lymphocytes that are abundant in the liver and participate in liver immunity. NKT cells express both NK cell and T cell markers, modulate innate and adaptive immune responses. Type I and Type II NKT cells are classified according to the TCR usage, while they recognize lipid antigen in a non-classical major histocompatibility (MHC) molecule CD1d-restricted manner. Once activated, NKT cells can quickly produce cytokines and chemokines to negatively or positively regulate the immune responses, depending on the different NKT subsets. In liver transplantation (LTx), the immune reactions in a series of processes determine the recipients' long-term survival, including ischemia-reperfusion injury, alloresponse, and post-transplant infection. This review provides insight into the research on NKT cells subpopulations in LTx immunity during different processes, and discusses the shortcomings of the current research on NKT cells. Additionally, the CD56-expressing T cells are recognized as a NK-like T cell population, they were also discussed during these processes.

Tracking DNA-based antigen-specific T cell receptors during progression to type 1 diabetes.

T cells targeting self-proteins are important mediators in autoimmune diseases. T cells express unique cell-surface receptors (TCRs) that recognize peptides presented by major histocompatibility molecules. TCRs have been identified from blood and pancreatic islets of individuals with type 1 diabetes (T1D). Here, we tracked ~1700 known antigen-specific TCR sequences, islet antigen or viral reactive, in bulk TCRβ sequencing from longitudinal blood DNA samples in at-risk cases who progressed to T1D, age/sex/human leukocyte antigen-matched controls, and a new-onset T1D cohort. Shared and frequent antigen-specific TCRβ sequences were identified in all three cohorts, and viral sequences were present across all ages. Islet sequences had different patterns of accumulation based upon antigen specificity in the at-risk cases. Furthermore, 73 islet-antigen TCRβ sequences were present in higher frequencies and numbers in T1D samples relative to controls. The total number of these disease-associated TCRβ sequences inversely correlated with age at clinical diagnosis, indicating the potential to use disease-relevant TCR sequences as biomarkers in autoimmune disorders.

A fluorescent reporter model for the visualization and characterization of TDC.

TDC are hematopoietic cells that combine dendritic cell (DC) and conventional T-cell markers and functional properties. They were identified in secondary lymphoid organs (SLOs) of naïve mice as cells expressing CD11c, major histocompatibility molecules (MHC)-II, and the T-cell receptor (TCR). Despite thorough characterization, a physiological role for TDC remains to be determined. Unfortunately, using CD11c as a marker for TDC has the caveat of its upregulation on different cells, including T cells, upon activation. Here, we took advantage of Zbtb46-GFP reporter mice to explore the frequency and localization of TDC in different tissues at steady state and upon viral infection. RNA sequencing analysis confirmed that TDC sorted from Zbtb46-GFP mice have a gene signature that is distinct from conventional T cells and DC. In addition, this reporter model allowed for identification of TDC in situ not only in SLOs but also in the liver and lung of naïve mice. Interestingly, we found that TDC numbers in the SLOs increased upon viral infection, suggesting that TDC might play a role during viral infections. In conclusion, we propose a visualization strategy that might shed light on the physiological role of TDC in several pathological contexts, including infection and cancer.

The role of bystander activation among CD8αα T cells in controlling Mycobacterium tuberculosisinfection

Abstract Classical cytotoxic T cells have a CD8 coreceptor with an αβ heterodimer and recognize peptide antigens via major histocompatibility (MHC) molecules. CD8 T cells with an αα homodimer structure are nonclassical and can recognize non-MHC molecules independently of antigen. CD8αα T cells have a higher propensity to undergo T cell receptor (TCR) independent bystander activation via pro-inflammatory cytokines. Bystander activation of CD8 T cells has shown a protective effect during Mycobacterium tuberculosis (M.tb) infection, but the distinct roles of CD8αα and CD8αβ T cells have not been elucidated. To begin assessing this, we compared the levels of CD8αα and CD8αβ T cell proliferation in response to TCR dependent stimulation using anti-CD3/CD28 beads. We observed that CD8αα T cells had lower levels of proliferation compared to CD8αβ T cells after three days of stimulation. After seven days, a population of CD8αα T cells did not proliferate while nearly all CD8αβ T cells showed high proliferative capacity. We next stimulated healthy peripheral blood mononuclear cells with IL-12, IL-15, and IL-18 to induce bystander activation and found 52.8% of CD8αα T cells secreted granzyme B compared to 25.1% of CD8αβ T cells. Interestingly, CD8αα T cells also had higher levels of CD69 expression than CD8αβ T cells (62.6% and 38.2%, respectively). Finally, we present plans for defining the role of bystander activated CD8αα and CD8αβ T cells during M.tb infection using tonsil organoids. These data reveal that CD8αα T cells have a distinct bimodal response to TCR mediated activation as well as an increased cytotoxic and activated phenotype after bystander activation. We further establish a foundation for future bystander activation studies in M.tb infection. Supported by grants from the NIH (R01 AI146072)

Immune response in pregnancy: An evolutionary challenge against external and internal stimuli

Immune response in pregnancy: An evolutionary challenge against external and internal stimuli

Immunoinformatic Evaluation of the Cross-presentation of Donor Major Histocompatibility Derived Epitopes by Recipient Major Histocompatibility Class I Molecules in Transplantation Rejection

Aim: The aim of this study was to analyze the cross-presentation of allopeptides derived from donor major histocompatibility (MHC) molecules by recipient class I MHC molecules in the context of transplantation rejection. Materials and Methods: The MHC molecules were selected based on frequency distribution in the Kerala (India) population using the “allelefrequency. net” database. The most frequent alleles were chosen as donor and recipient alleles. Different immunoinformatics servers such as Netcytotoxic T lymphocyte, NetMHCpan, and Immune Epitope Database MHC I were used for predicting potential T-cell epitopes, and MHC class I epitopes, respectively, from the chosen donor MHC molecule. Three peptides with strong binding affinities in all three predictions were selected for further analysis. The binding of these peptides to the second MHC class I molecule, the recipient one, and transporter associated with antigen processing protein was confirmed by molecular docking using the “AutoDockVina” tool. The binding interactions were visualized using the “Discovery Studio Visualizer” platform. Results: The ability of the selected class I MHC molecule, human leukocyte antigens (HLAs)-A* 11:01, considered the donor allele, to act as an exogenous antigen and to get processed into peptides and presented on the second class I MHC molecule, HLA-A*02:01, considered the recipient allele was confirmed. This immunoinformatics approach could help us to identify potential epitopes from an HLA class I molecule and to measure its ability to get cross-presented on a second HLA class I molecule to trigger the process of cell-mediated rejection. Conclusion: This immunoinformatics approach could help us to identify potential epitopes from an HLA class I molecule and to measure its ability to get cross-presented on a second HLA class I molecule to trigger the process of cell-mediated rejection. Our study provides an easy in silico method for predicting the chances of cell mediated rejection in organ transplantations involving an unrelated donor. We hope that this computational analysis will pave the way for simplifying the process involved in organ rejection prediction.

EPIPOX: A Resource Facilitating Epitope-Vaccine Design Against Human Pathogenic Orthopoxviruses.

EPIPOX is a specialized online resource intended to facilitate the design of epitope-based vaccines against orthopoxviruses. EPIPOX is built upon a collection of T cell epitopes that are shared by eight pathogenic orthopoxviruses, including variola minor and majorstrains, monkeypox, cowpox, and vaccinia viruses. In EPIPOX, users can select T cell epitopes attending to the predicted binding to distinct major histocompatibility molecules (MHC) and according to various features that may have an impact on epitope immunogenicity. Among others, EPIPOX allows to discern epitopes by their structural location in the virion and the temporal expression of the counterpart antigens. Overall, the annotations in EPIPOX are optimized to facilitate the rational design of T cell epitope-based vaccines. In this chapter, we describe the main features of EPIPOX and exemplify its use, retrieving orthopoxvirus-specific T cell epitopes with features set to enhance their immunogenicity. EPIPOX is available for free public use at http://bio.med.ucm.es/epipox/ .

Prediction of Peptide and TCR CDR3 Loops in Formation of Class I MHC-Peptide-TCR Complexes Using Molecular Models with Solvation.

Formation of major histocompatibility (MHC)-peptide-T cell receptor (TCR) complexes is central to initiation of an adaptive immune response. These complexes form through initial stabilization of the MHC fold via binding of a short peptide, and subsequent interaction of the TCR to form a ternary complex, with contacts made predominantly through the complementarity-determining region (CDR) loops of the TCR. Stimulation of an immune response is central to cancer immunotherapy. This approach depends on identification of the appropriate combinations of MHC molecules, peptides, and TCRs to elicit an antitumor immune response. This prediction is a current challenge in computational biochemistry. In this chapter, we introduce a predictive method that involves generation of multiple peptides and TCR CDR 3 loop conformations, solvation of these conformers in the context of the MHC-peptide-TCR ternary complex, extraction of parameters from the generated complexes, and use of an AI model to evaluate the potential for the assembled ternary complex to support an immune response.

MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas

Combining multiple therapeutic strategies in NRAS/BRAF mutant melanoma-namely MEK/BRAF kinase inhibitors, immune checkpoint inhibitors (ICIs), and targeted immunotherapies-may offer an improved survival benefit by overcoming limitations associated with any individual therapy. Still, optimal combination, order, and timing of administration remains under investigation. Here, we measure how MEK inhibition (MEKi) alters anti-tumor immunity by utilizing quantitative immunopeptidomics to profile changes in the peptide major histocompatibility molecules (pMHC) repertoire. These data reveal a collection of tumor antigens whose presentation levels are selectively augmented following therapy, including several epitopes present at over 1,000 copies per cell. We leveraged the tunable abundance of MEKi-modulated antigens by targeting four epitopes with pMHC-specific T cell engagers and antibody drug conjugates, enhancing cell killing in tumor cells following MEK inhibition. These results highlight drug treatment as a means to enhance immunotherapy efficacy by targeting specific upregulated pMHCs and provide a methodological framework for identifying, quantifying, and therapeutically targeting additional epitopes of interest.

Genetic resilience in chickens against bacterial, viral and protozoal pathogens.

The genome contributes to the uniqueness of an individual breed, and enables distinctive characteristics to be passed from one generation to the next. The allelic heterogeneity of a certain breed results in a different response to a pathogen with different genomic expression. Disease resistance in chicken is a polygenic trait that involves different genes that confer resistance against pathogens. Such resistance also involves major histocompatibility (MHC) molecules, immunoglobulins, cytokines, interleukins, T and B cells, and CD4+ and CD8+ T lymphocytes, which are involved in host protection. The MHC is associated with antigen presentation, antibody production, and cytokine stimulation, which highlight its role in disease resistance. The natural resistance-associated macrophage protein 1 (Nramp-1), interferon (IFN), myxovirus-resistance gene, myeloid differentiation primary response 88 (MyD88), receptor-interacting serine/threonine kinase 2 (RIP2), and heterophile cells are involved in disease resistance and susceptibility of chicken. Studies related to disease resistance genetics, epigenetics, and quantitative trait loci would enable the identification of resistance markers and the development of disease resistance breeds. Microbial infections are responsible for significant outbreaks and have blighted the poultry industry. Breeding disease-resistant chicken strains may be helpful in tackling pathogens and increasing the current understanding on host genetics in the fight against communicable diseases. Advanced technologies, such as the CRISPR/Cas9 system, whole genome sequencing, RNA sequencing, and high-density single nucleotide polymorphism (SNP) genotyping, aid the development of resistant breeds, which would significantly decrease the use of antibiotics and vaccination in poultry. In this review, we aimed to reveal the recent genetic basis of infection and genomic modification that increase resistance against different pathogens in chickens.

Nanoparticle formulation of the fusion protein virus like particles of respiratory syncytial virus stimulates enhanced in vitro antigen presentation and autophagy

Respiratory Syncytial Virus (RSV) is one of the leading causes of bronchiolitis and pneumonia in childrenunder one year globally. As a result, RSV poses a severe burden on healthcare services. Thus, a vaccine for RSV is a global need. Utilizing polymeric nanoparticles as a delivery system for vaccine antigen holds a lot of promise. In this study, the virus like particles of RSV fusion protein (F-VLP) was encapsulated in poly (D, L-lactide-co-glycolide) (PLGA) nanoparticles (NP). The F-VLP NP was formulated using a double emulsion solvent evaporation technique. The optimized NPs had a particle size of 525 ± 10.5 nm and an antigen encapsulation efficiency of 73% ± 10.5. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis showed that the F-VLP was stable post formulation. The F-VLP NP showed a sustained release of the F-VLP antigen for up to a week. In vitro study revealed that the F-VLP NP were non-cytotoxic, and the cellular uptake of the NPs by dendritic cells was observed within 3 h. The F-VLP NP with adjuvant monophosphoryl lipid A (MPL) NP and without MPL NP showed enhanced expression of antigen presentation molecule major histocompatibility complex (MHC)-I and autophagosomes in dendritic cells. In summary, the sustained release of the antigen from the F-VLP NP and the particulate nature of the vaccine resulted in enhanced antigen presentation and induction of autophagy in antigen-presenting cells (APCs).

Immunoinformatics approach of epitope prediction for SARS-CoV-2

BackgroundThe novel coronavirus (SARS-CoV-2) caused lethal infections worldwide during an unprecedented pandemic. Identification of the candidate viral epitopes is the first step in the design of vaccines against the viral infection. Several immunoinformatic approaches were employed to identify the SARS-CoV-2 epitopes that bind specifically with the major histocompatibility molecules class I (MHC-I). We utilized immunoinformatic tools to analyze the whole viral protein sequences, to identify the SARS-CoV-2 epitopes responsible for binding to the most frequent human leukocyte antigen (HLA) alleles in the Egyptian population. These alleles were also found with high frequency in other populations worldwide. ResultsMolecular docking approach showed that using the co-crystallized MHC-I and T cell receptor (TCR) instead of using MHC-I structure only, significantly enhanced docking scores and stabilized the conformation, as well as the binding affinity of the identified SARS-CoV-2 epitopes. Our approach directly predicts 7 potential vaccine subunits from the available SARS-CoV-2 spike and ORF1ab protein sequence. This prediction has been confirmed by published experimentally validated and in silico predicted spike epitope. On the other hand, we predicted novel epitopes (RDLPQGFSA and FCLEASFNY) showing high docking scores and antigenicity response with both MHC-I and TCR. Moreover, antigenicity, allergenicity, toxicity, and physicochemical properties of the predicted SARS-CoV-2 epitopes were evaluated via state-of-the-art bioinformatic approaches, showing high efficacy of the proposed epitopes as a vaccine candidate. ConclusionOur predicted SARS-CoV-2 epitopes can facilitate vaccine development to enhance the immunogenicity against SARS-CoV-2 and provide supportive data for further experimental validation. Our proposed molecular docking approach of exploiting both MHC and TCR structures can be used to identify potential epitopes for most microbial pathogens, provided the crystal structure of MHC co-crystallized with TCR.

T-cell Receptor Is a Threshold Detector: Sub- and Supra-Threshold Stochastic Resonance in TCR-MHC Clusters on the Cell Surface.

Stochastic resonance in clusters of major histocompatibility molecules is extended by a more detailed description of adaptive thresholding and by applying the notion of suprathreshold stochastic resonance as a stochastically quantizing encoder of transmembrane signaling downstream of major histocompatibility molecules and T-cell receptors on the side of presenting and recognizing cells, respectively. The adaptive nature of thresholding is partly explained by a mirroring of the noncognate–cognate dichotomy shown by the T-cell receptor structure and the kinetic-segregation model of the onset of T-cell receptor triggering. Membrane clusters of major histocompatibility molecules and T-cell receptors on their host cells are envisioned as places of the temporal encoding of downstream signals via the suprathreshold stochastic resonance process. The ways of optimization of molecular prostheses, such as chimeric antigen receptors against cancer in transmembrane signaling, are suggested in the framework of suprathreshold stochastic resonance. The analogy between Förster resonance energy transfer and suprathreshold stochastic resonance for information transfer is also discussed. The overlap integral for energy transfer parallels the mutual information transferred by suprathreshold stochastic resonance.

The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation

The monomorphic antigen-presenting molecule major histocompatibility complex-I-related protein 1 (MR1) presents small-molecule metabolites to mucosal-associated invariant T (MAIT) cells. The MR1-MAIT cell axis has been implicated in a variety of infectious and noncommunicable diseases, and recent studies have begun to develop an understanding of the molecular mechanisms underlying this specialized antigen presentation pathway. However, proteins regulating MR1 folding, loading, stability, and surface expression remain to be identified. Here, we performed a gene trap screen to discover novel modulators of MR1 surface expression through insertional mutagenesis of an MR1-overexpressing clone derived from the near-haploid human cell line HAP1 (HAP1.MR1). The most significant positive regulators identified included β2-microglobulin, a known regulator of MR1 surface expression, and ATP13A1, a P5-type ATPase in the endoplasmic reticulum (ER) not previously known to be associated with MR1-mediated antigen presentation. CRISPR/Cas9-mediated knockout of ATP13A1 in both HAP1.MR1 and THP-1 cell lines revealed a profound reduction in MR1 protein levels and a concomitant functional defect specific to MR1-mediated antigen presentation. Collectively, these data are consistent with the ER-resident ATP13A1 being a key posttranscriptional determinant of MR1 surface expression.

Molecular background of impairments in skeletal muscle of heart failure patients

Abstract Background Heart failure (HF) is characterised by systematic inflammation and chronic metabolic dysregulation. HF enhances the release of pro-inflammatory cytokines, induces activation of the complement system, production of autoantibodies, and over-expression of the major histocompatibility (MHC) complex class II molecules. It is known that skeletal muscles are exposed to the immunologic injury in disease; and muscle tissue appeared to be affected by HF leading to the muscle weakness and exercise intolerance development. However, molecular abnormalities occurring in HF patients' muscles and the mechanisms underlying its development are not clarified. Purpose To understand the molecular mechanisms underlying skeletal muscle immune and non-immune impairments in HF. Methods 8 health donors and 5 HF patients with reduced ejection fraction (NYHA Class II and III) were enrolled in this study in accordance with the principles under the Declaration of Helsinki (1989). mRNA of skeletal muscle biopsies of gastrocnemius lateralis were sequenced on Illumina HiSeq. RNA-seq analysis was performed using STAR with reference genome GRCh38 and featureCounts program; differentially expressed genes (DEGs) were assessed using R package DESeq2 with FDR=0.01 and log2 fold change (l2fc) >1.5 filter; pathway analysis was performed using clusterProfiler in R (FDR=0.01). Results 1404 differentially expressed genes distinguish muscles of HF patients and controls. Among upregulated genes there are different classical MHC molecules and specific one HLA-G (l2fc=2) that has been previously shown appeared in muscles under autoimmune myopathies, and potentially protect them. Unregulated DEGs were responsible for the activation of many molecular immunological pathways: type I interferon signaling pathway (16 DEGs out of total 89), regulation of T cell proliferation (14/153), neutrophil degranulation (31/485), granulocyte differentiation (7/32), negative regulation of viral process (11/53), that indicates about specific inflammatory response in HF muscles. Response to hypoxia (22/314) and gluconeogenesis pathways (12/87) were also activated. Downregulated genes include SLC5A1 (l2fc=−4) sodium glucose cotransporter; NRP3 (l2fc=−4) that plays a role in modulating intravascular volume and vascular tone; MMP1 (l2fc=−13) involved in the breakdown of extracellular matrix; the expression of many genes responsible for DNA-repair (44/534) and cilium assembly (34/366) was also suppressed. Conclusion Transcriptome analysis shows immunological and non-immunological alterations in HF skeletal muscles and provides the information about molecular mechanisms of its development. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Russian Science Foundation grant

No evidence that HLA genotype influences the driver mutations that occur in cancer patients

The major histocompatibility (MHC) molecules are capable of presenting neoantigens resulting from somatic mutations on cell surfaces, potentially directing immune responses against cancer. This led to the hypothesis that cancer driver mutations may occur in gaps in the capacity to present neoantigens that are dependent on MHC genotype. If this is correct, it has important implications for understanding oncogenesis and may help to predict driver mutations based on genotype data. In support of this hypothesis, it has been reported that driver mutations that occur frequently tend to be poorly presented by common MHC alleles and that the capacity of a patient’s MHC alleles to present the resulting neoantigens is predictive of the driver mutations that are observed in their tumor. Here we show that these reports of a strong relationship between driver mutation occurrence and patient MHC alleles are a consequence of unjustified statistical assumptions. Our reanalysis of the data provides no evidence of an effect of MHC genotype on the oncogenic mutation landscape.

The Role of Heat Shock Proteins in Type 1 Diabetes.

Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease characterized by recognition of pancreatic β-cell proteins as self-antigens, called autoantigens (AAgs), followed by loss of pancreatic β-cells. (Pre-)proinsulin ([P]PI), glutamic acid decarboxylase (GAD), tyrosine phosphatase IA-2, and the zinc transporter ZnT8 are key molecules in T1D pathogenesis and are recognized by autoantibodies detected in routine clinical laboratory assays. However, generation of new autoantigens (neoantigens) from β-cells has also been reported, against which the autoreactive T cells show activity. Heat shock proteins (HSPs) were originally described as “cellular stress responders” for their role as chaperones that regulate the conformation and function of a large number of cellular proteins to protect the body from stress. HSPs participate in key cellular functions under both physiological and stressful conditions, including suppression of protein aggregation, assisting folding and stability of nascent and damaged proteins, translocation of proteins into cellular compartments and targeting irreversibly damaged proteins for degradation. Low HSP expression impacts many pathological conditions associated with diabetes and could play a role in diabetic complications. HSPs have beneficial effects in preventing insulin resistance and hyperglycemia in type 2 diabetes (T2D). HSPs are, however, additionally involved in antigen presentation, presenting immunogenic peptides to class I and class II major histocompatibility molecules; thus, an opportunity exists for HSPs to be employed as modulators of immunologic responses in T1D and other autoimmune disorders. In this review, we discuss the multifaceted roles of HSPs in the pathogenesis of T1D and in autoantigen-specific immune protection against T1D development.

Human mucosal-associated invariant T cells respond to Mucorales species in a MR1-dependent manner.

Activation of mucosal-associated invariant T cells (MAIT cells) by certain bacteria, viruses, and yeast is well studied, but the activation potential of filamentous moulds from the order Mucorales is not known. Here, we show a rapid response of human MAIT cells against the Mucorales species Mucor circinelloides, Rhizopus arrhizus, and Rhizopus microsporus. This activation included upregulation of CD69 and degranulation marked by increased CD107a expression, while intracellular perforin and granzyme A expression were reduced. Furthermore, blocking of the antigen-presenting molecule major histocompatibility complex class I-related abrogated MAIT cell activation demonstrating a T cell receptor-dependent stimulation by Mucorales.

A bibenzyl compound 20C protects rats against 6-OHDA-induced damage by regulating adaptive immunity associated molecules

Parkinson's disease (PD) is a neurodegenerative disease with complicated pathogenesis. A novel bibenzyl compound 2-[4-hydroxy-3-(4-hydroxyphenyl)benzyl]-4-(4-hydroxyphenyl)phenol (20C) has been shown to have some neuroprotective effects, and its mechanism still needs further research. In this study, we used a 6-hydroxydopamine (6-OHDA)-induced PD rat model to evaluate the protective effect of 20C. Our study found that 20C could improve behavioral defects in 6-OHDA-lesion rats, decrease neuroinflammation and protect their DA neurons. It could inhibit the activity of inducible nitric oxide synthase (iNOS) induced by 6-OHDA, and lead to a decrease in the expression of nitrated-α-synuclein. When exposed to AMT-an inhibitor of iNOS, the nitrated-α-synuclein in PC12 decreased, and 20C demonstrated the same function on nitrated-α-synuclein as AMT. Besides, we also found that nitrated-α-synuclein was displayed in microglia. And 20C could decrease the expression of antigen-presenting molecule major histocompatibility complex I (MHC I) in dopamine (DA) neurons and MHC II in microglia induced by 6-OHDA. So, these imply that nitrated-α-synuclein might act as an endogenous antigen activating adaptive immunity, and the neuroprotection of 20C might be associated with inhibiting the activity of iNOS, decreasing the expression of the antigen molecule nitrated-α-synuclein and the antigen presenting molecule MHC. Our results indicated that inhibiting iNOS might be an effective strategy to protect neurons from oxidative stress.

In vivo detection of antigen-specific CD8+ T cells by immuno-positron emission tomography.

The immune system’s ability to recognize peptides on major histocompatibility molecules (pMHCs) contributes to eradication of cancers and pathogens. Tracking these responses in vivo could help evaluate the efficacy of immune interventions and improve mechanistic understanding of immune responses. We employ synTacs, dimeric pMHC scaffolds of defined composition, which enable clonal-selective delivery of a variety of signaling, recruitment, and imaging modalities. We show that synTacs, when labeled with positron-emitting isotopes, can non-invasively image antigen-specific CD8 T cells in vivo. We imaged human papillomavirus (HPV16) E7-specific CD8 T cells by positron emission tomography with an HPV16 E7 peptide-loaded synTac in HPV16-positive tumors, following administration of a therapeutic vaccine. We also imaged influenza A virus (IAV) nucleoprotein-specific CD8 T cells in the lungs of IAV-infected mice, using an isotopically labeled flu-specific synTac. It is thus possible to visualize antigen-specific CD8 T cell populations in vivo, which may serve prognostic and diagnostic roles.