scholarly journals Inflammation in multiple sclerosis

2021 ◽  
Vol 14 ◽  
pp. 175628642110076
Author(s):  
Stefanie Haase ◽  
Ralf A. Linker
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
B Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Myeloid Cells ◽  
Cell Types ◽  
Disease Modifying Therapies ◽  
Disease Modifying ◽  
Anti Inflammatory

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that is characterised pathologically by demyelination, gliosis, neuro-axonal damage and inflammation. Despite intense research, the underlying pathomechanisms driving inflammatory demyelination in MS still remain incompletely understood. It is thought to be caused by an autoimmune response towards CNS self-antigens in genetically susceptible individuals, assuming autoreactive T cells as disease-initiating immune cells. Yet, B cells were recognized as crucial immune cells in disease pathology, including antibody-dependent and independent effects. Moreover, myeloid cells are important contributors to MS pathology, and it is becoming increasingly evident that different cell types act in concert during MS immunopathology. This is supported by the finding that the beneficial effects of actual existing disease-modifying therapies cannot be attributed to one single immune cell-type, but rather involve immunological cooperation. The current strategy of MS therapies thus aims to shift the immune cell repertoire from a pro-inflammatory towards an anti-inflammatory phenotype, involving regulatory T and B cells and anti-inflammatory macrophages. Although no existing therapy actually exists that directly induces an enhanced regulatory immune cell pool, numerous studies identified potential net effects on these cell types. This review gives a conceptual overview on T cells, B cells and myeloid cells in the immunopathology of relapsing-remitting MS and discusses potential contributions of actual disease-modifying therapies on these immune cell phenotypes.

Single Cell Profiling Reveals Unique CXCL13 Positive T Cell Subsets in the Tumor Microenvironment of Lymphocyte Rich Classic Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Tomohiro Aoki ◽  
Lauren C. Chong ◽  
Katsuyoshi Takata ◽  
Katy Milne ◽  
Elizabeth Chavez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Single Cell ◽  
Immune Cells ◽  
Research Funding ◽  
Immune Cell ◽  
Expression Patterns ◽  
The Other ◽  
Tfh Cells

Introduction: Classic Hodgkin lymphoma (CHL) features a unique crosstalk between malignant cells and different types of normal immune cells in the tumor-microenvironment (TME). On the basis of histomorphologic and immunophenotypic features of the malignant Hodgkin and Reed-Sternberg (HRS) cells and infiltrating immune cells, four histological subtypes of CHL are recognized: Nodular sclerosing (NS), Mixed cellularity, Lymphocyte-rich (LR) and Lymphocyte-depleted CHL. Recently, our group described the high abundance of various types of immunosuppressive CD4+ T cells including LAG3+ and/or CTLA4+ cells in the TME of CHL using single cell RNA sequencing (scRNAseq). However, the TME of LR-CHL has not been well characterized due to the rarity of the disease. In this study, we aimed at characterizing the immune cell profile of LR-CHL at single cell resolution. METHODS: We performed scRNAseq on cell suspensions collected from lymph nodes of 28 primary CHL patients, including 11 NS, 9 MC and 8 LR samples, with 5 reactive lymph nodes (RLN) serving as normal controls. We merged the expression data from all cells (CHL and RLN) and performed batch correction and normalization. We also performed single- and multi-color immunohistochemistry (IHC) on tissue microarray (TMA) slides from the same patients. In addition, an independent validation cohort of 31 pre-treatment LR-CHL samples assembled on a TMA, were also evaluated by IHC. Results: A total of 23 phenotypic cell clusters were identified using unsupervised clustering (PhenoGraph). We assigned each cluster to a cell type based on the expression of genes described in published transcriptome data of sorted immune cells and known canonical markers. While most immune cell phenotypes were present in all pathological subtypes, we observed a lower abundance of regulatory T cells (Tregs) in LR-CHL in comparison to the other CHL subtypes. Conversely, we found that B cells were enriched in LR-CHL when compared to the other subtypes and specifically, all four naïve B-cell clusters were quantitatively dominated by cells derived from the LR-CHL samples. T follicular helper (TFH) cells support antibody response and differentiation of B cells. Our data show the preferential enrichment of TFH in LR-CHL as compared to other CHL subtypes, but TFH cells were still less frequent compared to RLN. Of note, Chemokine C-X-C motif ligand 13 (CXCL13) was identified as the most up-regulated gene in LR compared to RLN. CXCL13, which is a ligand of C-X-C motif receptor 5 (CXCR5) is well known as a B-cell attractant via the CXCR5-CXCL13 axis. Analyzing co-expression patterns on the single cell level revealed that the majority of CXCL13+ T cells co-expressed PD-1 and ICOS, which is known as a universal TFH marker, but co-expression of CXCR5, another common TFH marker, was variable. Notably, classical TFH cells co-expressing CXCR5 and PD-1 were significantly enriched in RLN, whereas PD-1+ CXCL13+ CXCR5- CD4+ T cells were significantly enriched in LR-CHL. These co-expression patterns were validated using flow cytometry. Moreover, the expression of CXCR5 on naïve B cells in the TME was increased in LR-CHL compared to the other CHL subtypes We next sought to understand the spatial relationship between CXCL13+ T cells and malignant HRS cells. IHC of all cases revealed that CXCL13+ T cells were significantly enriched in the LR-CHL TME compared to other subtypes of CHL, and 46% of the LR-CHL cases showed CXCL13+ T cell rosettes closely surrounding HRS cells. Since PD-1+ T cell rosettes are known as a specific feature of LR-CHL, we confirmed co-expression of PD-1 in the rosetting cells by IHC in these cases. Conclusions: Our results reveal a unique TME composition in LR-CHL. LR-CHL seems to be distinctly characterized among the CHL subtypes by enrichment of CXCR5+ naïve B cells and CD4+ CXCL13+ PD-1+ T cells, indicating the importance of the CXCR5-CXCL13 axis in the pathogenesis of LR-CHL. Figure Disclosures Savage: BeiGene: Other: Steering Committee; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy. Scott:Janssen: Consultancy, Research Funding; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy. Steidl:AbbVie: Consultancy; Roche: Consultancy; Curis Inc: Consultancy; Juno Therapeutics: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding.

scholarly journals Immune cell composition in normal human kidneys

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jun-Gyu Park ◽  
Myeongsu Na ◽  
Min-Gang Kim ◽  
Su Hwan Park ◽  
Hack June Lee ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Kidney Diseases ◽  
Myeloid Cells ◽  
Human Kidney ◽  
Effector Memory ◽  
Immune Cell Subsets ◽  
Immunological Mechanisms ◽  
Normal Human

Abstract An understanding of immunological mechanisms in kidney diseases has advanced using mouse kidneys. However, the profiling of immune cell subsets in human kidneys remains undetermined, particularly compared with mouse kidneys. Normal human kidneys were obtained from radically nephrectomised patients with urogenital malignancy (n = 15). Subsequently, human kidney immune cell subsets were analysed using multicolor flow cytometry and compared with subsets from C57BL/6 or BALB/c mice under specific pathogen-free conditions. Twenty kidney sections from healthy kidney donors or subjects without specific renal lesions were additionally analysed by immunohistochemistry. In human kidneys, 47% ± 12% (maximum 63%) of immune cells were CD3+ T cells. Kidney CD4+ and CD8+ T cells comprised 44% and 56% of total T cells. Of these, 47% ± 15% of T cells displayed an effector memory phenotype (CCR7− CD45RA− CD69−), and 48% ± 19% were kidney-resident cells (CCR7− CD45RA− CD69+). However, the proportions of human CD14+ and CD16+ myeloid cells were approximately 10% of total immune cells. A predominance of CD3+ T cells and a low proportion of CD14+ or CD68+ myeloid cells were also identified in healthy human kidney sections. In mouse kidneys, kidney-resident macrophages (CD11blow F4/80high) were the most predominant subset (up to 50%) but the proportion of CD3+ T cells was less than 20%. These results will be of use in studies in which mouse results are translated into human cases under homeostatic conditions or with disease.

P151 DISRUPTION OF ENDOGENOUS ITACONATE PRODUCTION EXACERBATES EXPERIMENTAL COLITIS

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S5-S6
Author(s):  
Ryan Frieler ◽  
Thomas Vigil ◽  
Richard Mortensen ◽  
Yatrik Shah
Keyword(s):  
Gene Expression ◽  
Immune Cell ◽  
Tricarboxylic Acid Cycle ◽  
Myeloid Cells ◽  
Experimental Colitis ◽  
Cell Types ◽  
Cell Phenotype ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Anti Inflammatory

Abstract Background Inflammation is a hallmark of inflammatory bowel disease and alterations in tricarboxylic acid cycle (TCA) metabolism have been identified as major regulators of immune cell phenotype during inflammation and hypoxia. The TCA cycle metabolite, itaconate, is produced by the enzyme aconitate decarboxylase 1 (Acod1) and is highly upregulated during classical macrophage activation and during experimental colitis. Itaconate and cell permeable derivatives have robust anti-inflammatory effects on macrophages, therefore we hypothesized that Acod1-produced itaconate has a protective, anti-inflammatory effect during experimental colitis. Methods and Results Wild type (WT) control and Acod1-/- mice were administered 3% Dextran Sulfate Sodium (DSS) in water for 7 days to induce experimental colitis. After DSS was discontinued, Acod1-/- mice had significantly reduced body weight recovery with increased macroscopic disease severity, and upon dissection had decreased colon length and more severe inflammation. To determine if myeloid cells are the critical Acod1/itaconate-producing cell types, we generated myeloid-specific Acod1 deficient mice, however no differences in weight loss, colon length or inflammatory gene expression were detected compared to WT controls. To test whether supplementation with exogenous itaconate could ameliorate colitis, WT mice were treated with the cell-permeable form of itaconate, dimethyl itaconate (DMI). Administration of DMI significantly improved recovery after 7 days of DSS treatment and significantly reduced inflammatory gene expression in the colon. Conclusion Our data suggest that Acod1-produced itaconate has an important role in the regulation of inflammation during experimental colitis. Although myeloid cells have been thought to be major producers of Acod1 and itaconate, our data indicate that other cell types are involved. These results highlight the importance of this immunometabolic pathway and suggest that preservation or enhancement of this pathway with natural metabolites or metabolite derivatives could have beneficial effects during colitis.

scholarly journals Selective Targeting of T and B Cell Populations by Alemtuzumab in the Treatment of Multiple Sclerosis

2017 ◽  
Vol 12 (02) ◽  
pp. 78
Author(s):  
Nikolaos C Grigoriadis ◽  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Types ◽  
Tolerability Profile ◽  
T And B Cells ◽  
Brain Volume Loss ◽  
Inflammatory Phenotype ◽  
B Cell Subsets

Upstream targeting of both T and B cells is a rational therapeutic approach in multiple sclerosis (MS) in view of how both cell types and the interaction between them contribute to MS pathophysiology. This article will discuss this new way of thinking in MS: the targeting of both T and B cells, with a focus on the recently developed therapy, alemtuzumab (Lemtrada®, Genzyme, UK). Alemtuzumab depletes T and B lymphocytes, mainly via complement-dependent cytolysis and antibody-dependent cytolysis; depletion of B cells is not an enduring effect compared with the depletion of T cells. After dosing, CD4+ and CD8+ T cells and CD19 B cells decrease initially but increase over the following 11 months. During repopulation after alemtuzumab treatment, there is a shift in the relative proportions of T cell and B cell subsets whereby proportions of regulatory T cells and memory-phenotype T cells are increased and the proportion of naive T cells is decreased. A switch from a pro- to an anti-inflammatory phenotype and cytokine profile caused by alemtuzumab may underpin the long-lasting suppression of MS activity that has been observed in clinical trials. Alemtuzumab treatment is also associated with a consistently good safety and tolerability profile. Further, alemtuzumab appears to promote neurorehabilitation by improving measures of physical functioning, disability, measures of quality of life, and brain volume loss. Alemtuzumab therefore has the potential to reduce disease burden and improve substantially the prognosis for patients with MS.

scholarly journals Multiplexed imaging of immune cells in staged multiple sclerosis lesions by mass cytometry

2019 ◽  
Author(s):  
Valeria Ramaglia ◽  
Salma Sheikh-Mohamed ◽  
Karen Legg ◽  
Olga L Rojas ◽  
Stephanie Zandee ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
B Cells ◽  
Immune Cells ◽  
Mass Cytometry ◽  
Simultaneous Imaging ◽  
Multiplexed Imaging ◽  
Cell Phenotypes ◽  
Brain And Spinal Cord ◽  
The Brain

ABSTRACTMultiple Sclerosis (MS) is characterized by demyelinated and inflammatory lesions in the brain and spinal cord. Lesions contain immune cells with variable phenotypes and functions. Here we use imaging mass cytometry (IMC) to enable the simultaneous imaging of 15+ proteins within 11 staged MS lesions. Using this approach, we demonstrated that the majority of demyelinating macrophage-like cells in active lesions were derived from the resident microglial pool. Although CD8+ T cells predominantly infiltrated the lesions, CD4+ T cells were also abundant but localized closer to blood vessels. B cells with a predominant switched memory phenotype were enriched across all lesion stages and were found to preferentially infiltrate the tissue as compared to unswitched B cells which localized to the vasculature. We propose that IMC will enable a comprehensive analysis of single-cell phenotypes, their functional states and cell-cell interactions in relation to lesion morphometry and demyelinating activity in the MS brain.

scholarly journals Knowledge-based classification of fine-grained immune cell types in single-cell RNA-Seq data with ImmClassifier

2020 ◽  
Author(s):  
Xuan Liu ◽  
Sara J.C. Gosline ◽  
Lance T. Pflieger ◽  
Pierre Wallet ◽  
Archana Iyer ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Effector Memory ◽  
Immune Cell Population ◽  
Fine Grained ◽  
Knowledge Based ◽  
Comparable Performance

AbstractSingle-cell RNA sequencing is an emerging strategy for characterizing the immune cell population in diverse environments including blood, tumor or healthy tissues. While this has traditionally been done with flow or mass cytometry targeting protein expression, scRNA-Seq has several established and potential advantages in that it can profile immune cells and non-immune cells (e.g. cancer cells) in the same sample, identify cell types that lack precise markers for flow cytometry, or identify a potentially larger number of immune cell types and activation states than is achievable in a single flow assay. However, scRNA-Seq is currently limited due to the need to identify the types of each immune cell from its transcriptional profile, which is not only time-consuming but also requires a significant knowledge of immunology. While recently developed algorithms accurately annotate coarse cell types (e.g. T cells vs macrophages), making fine distinctions has turned out to be a difficult challenge. To address this, we developed a machine learning classifier called ImmClassifier that leverages a hierarchical ontology of cell type. We demonstrate that ImmClassifier outperforms other tools (+20% recall, +14% precision) in distinguishing fine-grained cell types (e.g. CD8+ effector memory T cells) with comparable performance on coarse ones. Thus, ImmClassifier can be used to explore more deeply the heterogeneity of the immune system in scRNA-Seq experiments.

scholarly journals Authentic Patient-Derived Hepatitis C Virus Infects and Productively Replicates in Primary CD4+and CD8+T LymphocytesIn Vitro

2017 ◽  
Vol 92 (3) ◽  
Author(s):  
Georgia Skardasi ◽  
Annie Y. Chen ◽  
Tomasz I. Michalak
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Lymphocytes ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Hcv Rna ◽  
Biophysical Properties

ABSTRACTAccumulated evidence indicates that immune cells can support the replication of hepatitis C virus (HCV) in infected patients and in culture. However, there is a scarcity of data on the degree to which individual immune cell types support HCV propagation and on characteristics of virus assembly. We investigated the ability of authentic, patient-derived HCV to infectin vitrotwo closely related but functionally distinct immune cell types, CD4+and CD8+T lymphocytes, and assessed the properties of the virus produced by these cells. The HCV replication system in intermittently mitogen-stimulated T cells was adapted to infect primary human CD4+or CD8+T lymphocytes. HCV replicated in both cell types although at significantly higher levels in CD4+than in CD8+T cells. Thus, the HCV RNA replicative (negative) strand was detected in CD4+and CD8+cells at estimated mean levels ± standard errors of the means of 6.7 × 102± 3.8 × 102and 1.2 × 102± 0.8 × 102copies/μg RNA, respectively (P< 0.0001). Intracellular HCV NS5a and/or core proteins were identified in 0.9% of CD4+and in 1.2% of CD8+T cells. Double staining for NS5a and T cell type-specific markers confirmed that transcriptionally competent virus replicated in both cell types. Furthermore, an HCV-specific protease inhibitor, telaprevir, inhibited infection in both CD4+and CD8+cells. The emergence of unique HCV variants and the release of HCV RNA-reactive particles with biophysical properties different from those of virions in plasma inocula suggested that distinct viral particles were assembled, and therefore, they may contribute to the pool of circulating virus in infected patients.IMPORTANCEAlthough the liver is the main site of HCV replication, infection of the immune system is an intrinsic characteristic of this virus independent of whether infection is symptomatic or clinically silent. Many fundamental aspects of HCV lymphotropism remain uncertain, including the degree to which different immune cells support infection and contribute to virus diversity. We show that authentic, patient-derived HCV productively replicatesin vitroin two closely related but functionally distinct types of T lymphocytes, CD4+and CD8+cells. The display of viral proteins and unique variants, the production of virions with biophysical properties distinct from those in plasma serving as inocula, and inhibition of replication by an antiviral agent led us to ascertain that both T cell subtypes supported virus propagation. Infection of CD4+and CD8+T cells, which are central to adaptive antiviral immune responses, can directly affect HCV clearance, favor virus persistence, and decisively influence the development and progression of hepatitis C.

scholarly journals Erythrocytes in multiple sclerosis – forgotten contributors to the pathophysiology?

2016 ◽  
Vol 2 ◽  
pp. 205521731664998
Author(s):  
Kira Groen ◽  
Vicki E Maltby ◽  
Katherine A Sanders ◽  
Rodney J Scott ◽  
Lotti Tajouri ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Autoimmune Disease ◽  
Genetic Predisposition ◽  
Immune Cells ◽  
Lymphocytic Infiltration ◽  
Disease Modifying Therapies ◽  
The Central Nervous System ◽  
Disease Modifying

Multiple sclerosis (MS) is an autoimmune disease characterised by lymphocytic infiltration of the central nervous system and subsequent destruction of myelin and axons. On the background of a genetic predisposition to autoimmunity, environmental triggers are assumed to initiate the disease. The majority of MS research has focused on the pathological involvement of lymphocytes and other immune cells, yet a paucity of attention has been given to erythrocytes, which may play an important role in MS pathology. The following review briefly summarises how erythrocytes may contribute to MS pathology through impaired antioxidant capacity and altered haemorheological features. The effect of disease-modifying therapies on erythrocytes is also reviewed. It may be important to further investigate erythrocytes in MS, as this could broaden the understanding of the pathological mechanisms of the disease, as well as potentially lead to the discovery of novel and innovative targets for future therapies.

scholarly journals Regulation of Immune Functions by Non-Neuronal Acetylcholine (ACh) via Muscarinic and Nicotinic ACh Receptors

2021 ◽  
Vol 22 (13) ◽  
pp. 6818
Author(s):  
Masato Mashimo ◽  
Yasuhiro Moriwaki ◽  
Hidemi Misawa ◽  
Koichiro Kawashima ◽  
Takeshi Fujii
Keyword(s):  
T Cells ◽  
B Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Immune Functions ◽  
Cell Functions ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Cellular And Humoral Immunity ◽  
Ach Receptors

Acetylcholine (ACh) is the classical neurotransmitter in the cholinergic nervous system. However, ACh is now known to regulate various immune cell functions. In fact, T cells, B cells, and macrophages all express components of the cholinergic system, including ACh, muscarinic, and nicotinic ACh receptors (mAChRs and nAChRs), choline acetyltransferase, acetylcholinesterase, and choline transporters. In this review, we will discuss the actions of ACh in the immune system. We will first briefly describe the mechanisms by which ACh is stored in and released from immune cells. We will then address Ca2+ signaling pathways activated via mAChRs and nAChRs on T cells and B cells, highlighting the importance of ACh for the function of T cells, B cells, and macrophages, as well as its impact on innate and acquired (cellular and humoral) immunity. Lastly, we will discuss the effects of two peptide ligands, secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) and hippocampal cholinergic neurostimulating peptide (HCNP), on cholinergic activity in T cells. Overall, we stress the fact that ACh does not function only as a neurotransmitter; it impacts immunity by exerting diverse effects on immune cells via mAChRs and nAChRs.

scholarly journals In Situ Characterization of Human Lymphoid Tissue Immune Cells by Multispectral Confocal Imaging and Quantitative Image Analysis; Implications for HIV Reservoir Characterization

2021 ◽  
Vol 12 ◽  
Author(s):  
Eirini Moysi ◽  
Perla M. Del Rio Estrada ◽  
Fernanda Torres-Ruiz ◽  
Gustavo Reyes-Terán ◽  
Richard A. Koup ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Immune Cells ◽  
Cd4 T Cells ◽  
Lymphoid Tissue ◽  
Immune Cell ◽  
Hiv Reservoir ◽  
Human Lymphoid Tissue

CD4 T cells are key mediators of adaptive immune responses during infection and vaccination. Within secondary lymphoid organs, helper CD4 T cells, particularly those residing in germinal centers known as follicular helper T cells (Tfh), provide critical help to B-cells to promote their survival, isotype switching and selection of high affinity memory B-cells. On the other hand, the important role of Tfh cells for the maintenance of HIV reservoir is well documented. Thus, interrogating and better understanding the tissue specific micro-environment and immune subsets that contribute to optimal Tfh cell differentiation and function is important for designing successful prevention and cure strategies. Here, we describe the development and optimization of eight multispectral confocal microscopy immunofluorescence panels designed for in depth characterization and immune-profiling of relevant immune cells in formalin-fixed paraffin-embedded human lymphoid tissue samples. We provide a comprehensive library of antibodies to use for the characterization of CD4+ T-cells -including Tfh and regulatory T-cells- as well as CD8 T-cells, B-cells, macrophages and dendritic cells and discuss how the resulting multispectral confocal datasets can be quantitatively dissected using the HistoCytometry pipeline to collect information about relative frequencies and immune cell spatial distributions. Cells harboring actively transcribed virus are analyzed using an in-situ hybridization assay for the characterization of HIV mRNA positive cells in combination with additional protein markers (multispectral RNAscope). The application of this methodology to lymphoid tissues offers a means to interrogate multiple relevant immune cell targets simultaneously at increased resolution in a reproducible manner to guide CD4 T-cell studies in infection and vaccination.

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