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bioRxiv2023

The prospect of universal coronavirus immunity: a characterization of reciprocal and non-reciprocal T cell responses against SARS-CoV2 and common human coronaviruses

T cell immunity plays a central role in clinical outcomes of Coronavirus Infectious Disease 2019 (COVID-19). Therefore, T cell-focused vaccination or cellular immunotherapy might provide enhanced protection for immunocompromised patients. Pre-existing T cell memory recognizing SARS-CoV2 antigens antedating COVID-19 infection or vaccination, may have developed as an imprint of prior infections with endemic non-SARS human coronaviruses (hCoVs) OC43, HKU1, 229E, NL63, pathogens of "common cold". In turn, SARS-CoV2-primed T cells may recognize emerging variants or other hCoV viruses and modulate the course of subsequent hCoV infections. Cross-immunity between hCoVs and SARS-CoV2 has not been well characterized. Here, we systematically investigated T cell responses against the immunodominant SARS-CoV2 spike, nucleocapsid and membrane proteins and corresponding antigens from - and {beta}-hCoVs among vaccinated, convalescent, and unexposed subjects. Broad T cell immunity against all tested SARS-CoV2 antigens emerged in COVID-19 survivors. In convalescent and in vaccinated individuals, SARS-CoV2 spike-specific T cells reliably recognized most SARS-CoV2 variants, however cross-reactivity against the omicron variant was reduced by approximately 50%. Responses against spike, nucleocapsid and membrane antigens from endemic hCoVs were more extensive in COVID-19 survivors than in unexposed subjects and displayed cross-reactivity between - and {beta}-hCoVs. In some, non-SARS hCoV-specific T cells demonstrated a prominent non-reciprocal cross-reactivity with SARS-CoV2 antigens, whereas a distinct anti-SARS-CoV2 immunological repertoire emerged post-COVID-19, with relatively limited cross-recognition of non-SARS hCoVs. Based on this cross-reactivity pattern, we established a strategy for in-vitro expansion of universal anti-hCoV T cells for adoptive immunotherapy. Overall, these results have implications for the future design of universal vaccines and cell-based immune therapies against SARS- and non-SARS-CoVs.

immunology↗

bioRxiv2023

Humanized CD36 mouse model supports the preclinical evaluation of therapeutic candidates targeting CD36

CD36 (also known as scavenger receptor B2) is a multifunctional receptor that mediates lipid uptake, advanced oxidation protein products, and immunological recognition, and has roles in lipid accumulation, apoptosis, as well as in metastatic colonization in cancer. CD36 is involved in tumor immunity, metastatic invasion, and therapy resistance through various molecular mechanisms. Targeting CD36 has emerged as an effective strategy for tumor immunotherapy. In this study, we have successfully generated a novel CD36 humanized mouse strain where the sequences encoding the extracellular domains of the mouse Cd36 gene were replaced with the corresponding human sequences. The results showed that CD36 humanized mice expressed only human CD36, and the proportion of each lymphocyte was not significantly changed compared with wild-type mice. Furthermore, CD36 monoclonal antibody could significantly inhibit tumor growth after treatment. Therefore, the CD36 humanized mice provided a validated preclinical mouse model for the evaluation of tumor immunotherapy targeting CD36.

immunology↗

bioRxiv2023

Microfluidics-enabled fluorescence-activated cell sorting of single pathogen-specific antibody secreting cells for the rapid discovery of monoclonal antibodies

Monoclonal antibodies are increasingly used to prevent and treat viral infections, playing a pivotal role in pandemic response efforts. Antibody secreting cells (ASCs, plasma cells and plasmablasts) are an excellent source of high-affinity antibodies with therapeutic potential. Current methodologies to study antigen-specific ASCs either have low throughput, require expensive and labour-intensive screening or are technically demanding and therefore not accessible to the wider research community. Here, we present a straightforward technology for the rapid discovery of monoclonal antibodies from ASCs: we combine microfluidic encapsulation of single cells into an antibody capture hydrogel with antigen bait sorting by conventional flow cytometry. With our technology, we screened millions of mouse and human ASCs and obtained anti-SARS-CoV-2 monoclonal antibodies with high affinity (pM) and neutralising capacity (<100 ng/mL) in two weeks with a high hit rate (>85%). By facilitating access into the underexplored ASC compartment, we enable fast and efficient antibody discovery as well as immunological studies into the generation of protective antibodies.

immunology↗

bioRxiv2023

Maintained imbalance of triglycerides, apolipoproteins, energy metabolites and cytokines in long-term COVID-19 syndrome (LTCS) patients

Deep metabolomic, proteomic and immunologic phenotyping of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients have matched a wide diversity of clinical symptoms with potential biomarkers for coronavirus disease 2019 (COVID-19). Within here, several studies described the role of metabolites, lipoproteins and inflammation markers during infection and in recovered patients. In fact, after SARS-CoV-2 viral infection almost 20-30% of patients experience persistent symptoms even after 12 weeks of recovery which has been defined as long-term COVID-19 syndrome (LTCS). Emerging evidence revealed that a dysregulated immune system and persisting inflammation could be one of the key drivers of LTCS. However, how these small biomolecules such as metabolites, lipoprotein, cytokines and chemokines altogether govern pathophysiology is largely underexplored. Thus, a clear understanding how these parameters into an integrated fashion could predict the disease course may help to stratify LTCS patients from acute COVID-19 or recovered specimen and would help to elucidate a potential mechanistic role of these biomolecules during the disease course. Here, we report an integrated analysis of blood serum and plasma by in vitro diagnostics research NMR spectroscopy and flow cytometry-based cytokine quantification in a total of 125 individuals (healthy controls (HC; n=73), recovered (n=12), acute (n=7) and LTCS (n=33)). We identified that in LTCS patients lactate and pyruvate were significantly different from either healthy controls or acute COVID-19 patients. Further correlational analysis of cytokines and metabolites indicated that creatine, glutamine, and high-density lipoprotein (HDL) phospholipids were distributed differentially amongst patients or individuals. Of note, triglycerides and several lipoproteins (apolipoproteins Apo-A1 and A2) in LTCS patients demonstrate COVID-19-like alterations compared to HC. Interestingly, LTCS and acute COVID-19 samples were distinguished mostly by their creatinine, phenylalanine, succinate, 3-hydroxybutyrate (3-HB) and glucose concentrations, illustrating an imbalanced energy metabolism. Most of the cytokines and chemokines were present at low levels in LTCS patients compared with HC except IL-18 chemokine, which tended to be higher in LTCS patients and correlated positively with several amino acids (creatine, histidine, leucine, and valine), metabolites (lactate and 3-HB) and lipoproteins. The identification of these persisting plasma metabolites, lipoprotein and inflammation alterations will help to better stratify LTCS patients from other diseases and could help to predict ongoing severity of LTCS patients. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/523998v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@ecdeacorg.highwire.dtl.DTLVardef@10f0f80org.highwire.dtl.DTLVardef@1c2ddaborg.highwire.dtl.DTLVardef@672120_HPS_FORMAT_FIGEXP M_FIG C_FIG Layman summary & significance of the researchAlmost 20-30% of individuals infected with the SARS-CoV-2 virus regardless of hospitalization status experience long-term COVID-19 syndrome (LTCS). It is devasting for millions of individuals worldwide and hardly anything is known about why some people experience these symptoms even after 3 to 12 months after the acute phase. In this, we attempted to understand whether dysregulated metabolism and inflammation could be contributing factors to the ongoing symptoms in LTCS patients. Total blood triglycerides and the Cory cycle metabolites (lactate and pyruvate) were significantly higher, lipoproteins (Apo-A1 and A2) were drastically lower in LTCS patients compared to healthy controls. Correlation analysis revealed that either age or gender are positively correlated with several metabolites (citrate, glutamate, 3-hydroxybutyrate, glucose) and lipoproteins (Apo-A1, HDL Apo-A1, LDL triglycerides) in LTCS patients. Several cytokines and chemokines were also positively correlated with metabolites and lipoproteins thus, dysregulation in metabolism and inflammation could be a potential contributory factor for LTCS symptoms.

immunology↗

bioRxiv2023

3D Chromatin Dynamics during Innate and Adaptive Immune Memory Acquisition

Immune cells responding to pathogens undergo molecular changes that are intimately linked to genome organization. Recent work has demonstrated that natural killer (NK) and CD8+ T cells experience substantial transcriptomic and epigenetic rewiring during their differentiation from naive to effector to memory cells. Whether these molecular adaptations are accompanied by changes in three-dimensional (3D) chromatin architecture is unknown. In this study, we combine histone profiling, ATAC-seq, RNA-seq and high-throughput chromatin capture (HiC) assay to investigate the dynamics of one-dimensional (1D) and 3D chromatin during the differentiation of innate and adaptive lymphocytes. To this end, we discovered a coordinated 1D and 3D epigenetic remodeling during innate immune memory differentiation, and demonstrate that effector CD8+ T cells adopt an NK-like architectural program that is maintained in memory cells. Altogether, our study reveals the dynamic nature of the 1D and 3D genome during the formation of innate and adaptive immunological memory.

immunology↗

bioRxiv2023

Immune-mediated tumor control in the 5TGM1 transfer model of multiple myeloma

Multiple myeloma is a disease of malignant plasma cells residing in the bone marrow, where interactions with local immune cells are thought to contribute to disease pathobiology. However, since a multiple myeloma diagnosis is virtually always preceded by an asymptomatic precursor phase, identifying early alterations in the bone marrow micro-environment following occupation by multiple myeloma cells remains challenging. Here we used the 5TGM1 transfer model of murine myeloma in combination with myeloma-permissive KaLwRij mice and myeloma-resistant C57Bl/6 mice and hypothesized that differential sensitivity to myeloma in these HLA-identical mouse strains has an immunological basis and might allow for dissection of early immune responses to myeloma cells. Using flow cytometry and single-cell RNA sequencing we show that C57Bl/6 mice can restrain tumor growth for prolonged periods, associated with activation of cytotoxic immune responses that were absent from KaLwRij mice. Transcriptional analysis of immune cells and stromal cells identified a central role for IFN-signaling in tumor containment, and antibody-mediated neutralization of IFN{gamma} increased both incidence and outgrowth of multiple myeloma in C57Bl/6 mice. Together these findings highlight the ability of a fully functional immune system to control multiple myeloma progression in an IFN{gamma}-dependent manner and suggest that transfer of 5TGM1 cells into parental C57Bl/6 mice can serve as a faithful model to track anti-myeloma immune responses in immune competent and genetically modifiable mice.

immunology↗

bioRxiv2023

RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection

Innate immune signaling in the central nervous system (CNS) exhibits many remarkable specializations that vary across cell types and CNS regions. In the setting of neuroinvasive flavivirus infection, neurons employ the immunologic kinase receptor-interacting kinase 3 (RIPK3) to promote an antiviral transcriptional program, independently of the traditional function of this enzyme in promoting necroptotic cell death. However, while recent work has established roles for neuronal RIPK3 signaling in controlling mosquito-borne flavivirus infections, including West Nile virus and Zika virus, functions for RIPK3 signaling in the CNS during tick-borne flavivirus infection have not yet been explored. Here, we use a model of Langat virus (LGTV) encephalitis to show that RIPK3 signaling is specifically required in neurons of the cerebellum to control LGTV replication and restrict disease pathogenesis. This effect did not require the necroptotic executioner molecule mixed lineage kinase domain like protein (MLKL), a finding similar to previous observations in models of mosquito-borne flavivirus infection. However, control of LGTV infection required a unique, region-specific dependence on RIPK3 to promote expression of key antiviral interferon-stimulated genes (ISG) in the cerebellum. This RIPK3- mediated potentiation of ISG expression was associated with robust cell-intrinsic restriction of LGTV replication in cerebellar granule cell neurons. These findings further illuminate the complex roles of RIPK3 signaling in the coordination of neuroimmune responses to viral infection, as well as provide new insight into the mechanisms of region-specific innate immune signaling in the CNS. ImportanceInteractions between the nervous and immune systems are very carefully orchestrated in order to protect the brain and spinal cord from immune-mediated damage, while still maintaining protective defenses against infection. These specialized neuro-immune interactions have been shown to vary significantly across regions of the brain, with innate antiviral signaling being particularly strong in the cerebellum, although the reasons for this are poorly understood. Here, we show a specialized adaptation of programmed cell death signaling that uniquely protects the cerebellum from tick-borne flavivirus infection. These findings provide important new insight into the molecular mechanisms that promote the uniquely robust antiviral immunity of the cerebellum. They also provide new clues into the pathogenesis of tick-borne encephalitis, a zoonosis of significant global concern.

immunology↗

bioRxiv2023

Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities

Inborn Errors of Metabolism (IEM) and Immunity (IEI) are Mendelian diseases in which complex phenotypes and patient rarity can limit clinical annotations. Few genes are assigned to both IEM and IEI, but immunometabolic demands suggest functional overlap is underestimated. We applied CRISPR screens to test IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable crossover. Analysis of IEM showed N-linked glycosylation and the de novo hexosamine synthesis enzyme, Gfpt1, are critical for T cell expansion and function. Interestingly, Gfpt1-deficient TH1 cells were more affected than TH17 cells, which had increased Nagk for salvage UDP-GlcNAc synthesis. Screening IEI genes showed the transcription factor Bcl11b promotes CD4+ T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. These data illustrate a high degree of functional overlap of IEM and IEI genes and point to potential immunometabolic mechanisms for a previously unappreciated set of these disorders. HIGHLIGHTSO_LIInborn errors of immunity and metabolism have greater overlap than previously known C_LIO_LIGfpt1 deficiency causes an IEM but also selectively regulates T cell subset fate C_LIO_LILoss of Bcl11b causes a T cell deficiency IEI but also harms mitochondrial function C_LIO_LIMany IEM may have immune defects and IEI may be driven by metabolic mechanisms C_LI

immunology↗

bioRxiv2023

Mass cytometry identifies dysregulation of circulating and cutaneous immune cells in patients with hidradenitis suppurativa

2.BackgroundHidradenitis suppurativa (HS) is a multifactorial, inflammatory skin disease. Increased systemic inflammatory comorbidities and serum cytokines highlight systemic inflammation as a feature of HS. However, the specific immune cell subsets contributing to systemic and cutaneous inflammation have not been resolved. ObjectiveIdentify features of peripheral and cutaneous immune dysregulation. MethodsHere, we generated whole-blood immunomes by mass cytometry. We performed a meta-analysis of RNA-seq data, immunohistochemistry, and imaging mass cytometry to characterize the immunological landscape of skin lesions and perilesions from patients with HS. ResultsBlood from patients with HS exhibited lower frequencies of natural killer cells, dendritic cells, and classical (CD14+CD16-) and nonclassical (CD14-CD16+) monocytes, as well as higher frequencies of Th17 cells and intermediate (CD14+CD16+) monocytes than blood from healthy controls. Classical and intermediate monocytes from patients with HS had increased expression of skin-homing chemokine receptors. Furthermore, we identified a CD38+ intermediate monocyte subpopulation that was more abundant in the immunome of blood from patients with HS. Meta-analysis of RNA-seq data found higher CD38 expression in lesional HS skin than in perilesional skin, and markers of classical monocyte infiltration. Imaging mass cytometry showed that CD38+ classical monocytes and CD38+ monocyte-derived macrophages were more abundant in lesional HS skin. ConclusionOverall, we report targeting CD38 may be worth pursuing in clinical trials. 3. Key MessagesO_LIMonocyte subsets express markers of activation in circulation and HS lesions C_LIO_LITargeting CD38 may be a viable strategy for treating systemic and cutaneous inflammation in patients with HS C_LI 4. Capsule SummaryDysregulated immune cells in patients with HS express CD38 and may be targeting by anti-CD38 immunotherapy.

immunology↗

bioRxiv2023

Tregs constrain CD8+ T cell priming required for curative intratumorally anchored anti-4-1BB immunotherapy

Although co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical development has been hampered by on-target, off-tumor toxicity. Here, we report the development of a tumor-anchored 4-1BB agonist (4-1BB-LAIR), which consists of an 4-1BB antibody fused to the collagen binding protein LAIR. While combination treatment with an antitumor antibody (TA99) displayed only modest efficacy, simultaneous depletion of CD4+ T cells boosted cure rates to over 90% of mice. We elucidated two mechanisms of action for this synergy: CD4 eliminated tumor draining lymph node Tregs, enhancing priming and activation of CD8+ T cells, and TA99 + 4-1BB-LAIR supported the cytotoxic program of these newly primed CD8+ T cells within the tumor microenvironment. Replacement of CD4 with CTLA-4, a clinically approved antibody that enhances T cell priming, produced equivalent cure rates while additionally generating robust immunological memory against secondary tumor rechallenge. One Sentence SummaryInhibition of nodal Tregs enhances CD8+ T cell priming, improving antitumor responses to collagen-anchored 4-1BB combination therapy.

immunology↗

bioRxiv2023

Imaging Architecture of Granulomas Induced by Mycobacterium tuberculosis Infections with Single-Molecule FISH

Granulomas are an important hallmark of Mycobacterium tuberculosis (Mtb) infection. They are organized and dynamic structures created by an assembly of immune cells around the sites of infection in the lungs to locally restrict the bacterial growth and the hosts inflammatory responses. The cellular architecture of granulomas is traditionally studied by immunofluorescence labeling of phenotypic surface markers. However, very few antibodies are available for model animals used in tuberculosis research, such as non-human primates and rabbits; secreted immunological markers such as cytokines cannot be imaged in situ using antibodies; and traditional phenotypic surface markers do not provide sufficient resolution for the detection of many subtypes and differentiation states of immune cells. Using single-molecule fluorescent in situ hybridization (smFISH) and its derivatives, amplified smFISH (ampFISH) and iterative smFISH, we developed a platform for imaging mRNAs encoding immune markers in rabbit and macaque tuberculosis granulomas. Multiplexed imaging for several mRNA and protein markers was followed by quantitative measurement of expression of these markers in single cells in situ. A quantitative analysis of combinatorial expressions of these markers allowed us to classify the cells into several subtypes and chart their distributions within granulomas. For one mRNA target, HIF-1, we were able to image its mRNA and protein in the same cells, demonstrating the specificity of probes. This method paves the way for defining granular differentiation states and cell subtypes from transcriptomic data, identifying key mRNA markers for these cell subtypes, and then locating the cells in the spatial context of granulomas.

immunology↗

bioRxiv2023

Seroprevalence of IgG Antibody against SARS-CoV-2 Nucleocapsid protein and Associated Risk Factors

Estimation of antibody development against SARS-CoV-2 is essential means for understanding the immune response against the virus. We reported IgG antibody development status against Nucleocapsid protein of the virus and compared with lifestyle (health and food habits), co-existing diseases, vaccination and COVID-19 infection status. ELISA (Enzyme Linked Immunosorbent Assay) was performed to assess IgG antibodies targeted against the Nucleocapsid protein of SARS-CoV-2 in participants (n=500). In this seroprevalence study, serological data were estimated for a period of 10 months in the participants who were aged 10 years and above. Sociodemographic and risk factors related data were collected through a written questionnaire and chi-square test was performed to determine the association with seropositivity. The overall seroprevalence of anti-SARS-CoV-2 antibodies among the study subjects was 47.8%. Estimates were highest among the participants of 21-40 years old (55.1%), and lowest in older aged (>60 years) participants (39.5%). Among the Sinopharm vaccinated individuals 81.8% had developed anti-Nucleocapsid antibody. Physical exercise and existence of comorbidities like hypertension and diabetes were the distinguishing factors between seropositive and seronegative individuals. Seropositivity rate largely varied among symptomatic (67%) and asymptomatic (33.1%) COVID-19 infected participants. The findings suggest that residents of Dhaka city had a higher prevalence of anti-nucleocapsid antibody in the second year of the pandemic. This indicates the improvement of immunological status among the population. Finally, the study emphasizes on maintaining active and healthy lifestyle to improve immunity. However, the absence of IgG antibodies in many cases of COVID-19 infected individuals suggests that antibodies wane with time. Key messagesO_LIThe overall seroprevalence of anti-Nucleocapsid IgG among the study subjects was determined to be 47.8%. C_LIO_LIAge, regular physical exercise, existence of comorbidities were the identified parameters associated with seroprevalence. C_LIO_LIThis study observed lower prevalence of Anti-Nucleocapsid antibody among asymptomatic cases of COVID-19 infected individuals compared to symptomatic cases. C_LI

immunology↗

bioRxiv2023

Imaging the immune synapse: three-dimensional analysis of the immune synapse

T cell receptor (TCR) stimulation of T lymphocytes by antigen bound to the major histocompatibility complex (MHC) of an antigen-presenting cell (APC), together with the interaction of accessory molecules, induces the formation of the immunological synapse (IS), the convergence of secretion vesicles towards the centrosome, and the polarization of the centrosome to the IS. Upon IS formation, an initial increase in cortical filamentous actin (F-actin) at the IS takes place, followed by a decrease in F-actin density at the central region of the IS, which contains the secretory domain. These reversible, cortical actin cytoskeleton reorganization processes that characterize a mature IS occur during lytic granule secretion in cytotoxic T lymphocytes (CTL) and cytokine-containing vesicle secretion in T-helper (Th) lymphocytes. Besides, IS formation constitutes the basis of a signalling platform that integrates signals and coordinates molecular interactions that are necessary for an appropriate antigen-specific immune response. In this chapter we deal with the three-dimensional (3D) analysis of the synaptic interface architecture, as well as the analysis of the localization of different markers at the IS.

immunology↗

bioRxiv2023

Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of Th17 immunity

Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+TCF1+ Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a novel Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue, and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.

immunology↗

bioRxiv2023

Epigenetic regulation of innate immune genes and enhanced interleukin-10 expression underlie chronic subclinical Plasmodium chabaudi infection

Subclinical (asymptomatic) parasitemia is very common amongst Plasmodium-infected individuals. The immunological mechanisms underlying subclinical parasitemia remain elusive. We investigated the immune regulatory mechanisms behind chronic asymptomatic Plasmodium infection using mice lacking humoral immunity ({micro}MT-/- mice). {micro}MT-/- mice became chronically infected, despite lacking outward signs of disease, and exhibited increased macrophage numbers, decreased dendritic and CD4 cells, massive hemozoin accumulation in the spleen and bone marrow, and inadequate hematopoiesis. These changes were accompanied by high circulating levels of interleukin-10 (IL-10), enhanced chromatin accessibility of the STAT3 promoter, and enhanced STAT3 binding to the IL-10 promoter in macrophages. Inhibition of IL-10 signaling, despite promoting parasite clearance, resulted in a proinflammatory response, weight loss, and mortality. These results suggest that epigenetic changes induced by chronic P. chabaudi infection lead to high levels of circulating IL-10, protecting chronically infected mice against an excessive inflammatory response to high levels of blood-stage parasites. Author summaryMalaria is a life-threatening disease with a range of symptoms, and it is induced in humans by infections with different species of Plasmodium. Highly prevalent in endemic regions, asymptomatic Plasmodium infections are related to long-term exposure to the parasite due to multiple infections and have been demonstrated in human and mouse studies to be associated with elevated levels of IL-10. However, how IL-10 levels remain elevated in the circulation in individuals over the long term has not been determined. We used a mouse model of chronic asymptomatic Plasmodium infection to investigate the mechanisms by which IL-10 levels are elevated during chronic asymptomatic infection. Our results show that epigenetic changes in immune genes of myeloid origin could be responsible for the elevated levels of IL-10, and that IL-10 signaling protected chronically infected mice from a severe inflammatory response induced by the infection.

immunology↗

bioRxiv2023

CTLA-4 antibody-drug conjugate reveals autologous destruction of B-lymphocytes associated with regulatory T cell impairment

Germline CTLA-4 deficiency causes severe autoimmune diseases characterized by dysregulation of Foxp3+ Tregs, hyper-activation of effector memory T cells, and variable forms autoimmune cytopenia including gradual loss of B cells. Cancer patients with severe immune-related adverse events (irAE) after receiving anti-CTLA-4/PD-1 combination immunotherapy also have markedly reduced peripheral B cells. The immunological basis for B cell loss remains unexplained. Here we probe the decline of B cells in human CTLA-4 knock-in mice by using anti-human CTLA-4 antibody Ipilimumab conjugated to a drug payload emtansine (Anti-CTLA-4 ADC). The anti-CTLA-4 ADC-treated mice have T cell hyper-proliferation and their differentiation into effector cells which results in B cell depletion. B cell depletion is mediated by both CD4 and CD8 T cells and at least partially rescued by anti-TNF-alpha antibody. These data revealed an unexpected antagonism between T and B cells and the importance of regulatory T cells in preserving B cells.

immunology↗

bioRxiv2023

CD8+ cells and small viral reservoirs facilitate post-ART control of SIV in Mauritian cynomolgus macaques

Sustainable HIV remission after antiretroviral therapy (ART) withdrawal, or post-treatment control (PTC), remains a top priority for HIV treatment. We observed surprising PTC in an MHC-haplomatched cohort of MHC-M3+ SIVmac239+ Mauritian cynomolgus macaques (MCMs) initiated on ART at two weeks post-infection (wpi). For six months after ART withdrawal, we observed undetectable or transient viremia in seven of eight MCMs. In vivo depletion of CD8+ cells induced rebound in all animals, indicating the PTC was mediated, at least in part, by CD8+ cells. We found that MCMs had smaller acute viral reservoirs than a cohort of identically infected rhesus macaques, a population that rarely develops PTC. The mechanisms by which unusually small viral reservoirs and CD8+ cell-mediated virus suppression enable PTC can be investigated using this MHC-haplomatched MCM model. Further, defining the immunologic mechanisms that engender PTC in this model may identify therapeutic targets for inducing durable HIV remission in humans.

immunology↗

bioRxiv2023

A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFβ

A rapid immune response to pathogen re-exposure underpins immunological memory, with protection against divergent pathogens such as heterologous or novel viral strains requiring cross-reactive memory T cells. Understanding the pathways that control memory T cell function is therefore important for the rational design of viral vaccines and will aid the discovery of therapies to boost anti-viral immunity. Here, we identify a sub-population of memory T cells that limit secondary immune responses to viral re-infection, which is crucial in preventing host tissue damage. We show that a population of CD4+ effector memory T (TEM) cells activate the important immunoregulatory cytokine TGF{beta}, via expression of an integrin, v{beta}8. Integrin v{beta}8 expression marks a transcriptionally distinct sub-population of CD4+ TEM, enriched for anti-inflammatory pathways. Loss of integrin v{beta}8 on murine CD4+ TEM, but not Foxp3+ regulatory T cells (TREG), led to exacerbated virus-specific CD8+ T cell responses following secondary influenza A virus (IAV) infection, which was associated with enhanced viral clearance. However, although accelerating clearance, loss of integrin v{beta}8 expression on CD4+ TEM resulted in enhanced lung pathology following secondary IAV infection, which was completely reversed by adoptive transfer of v{beta}8+ CD4+ TEM cells. These data highlight a new pathway by which a distinct CD4+ memory T cell subset restrains anti-viral immunity to prevent host tissue damage during secondary viral infection. Such pathways could be targeted therapeutically to either boost memory T-cell-mediated immunity or restrain host tissue damage during viral infection.

immunology↗