Subclinical Cytomegalovirus Infection Is Associated with Altered Host Immunity, Gut Microbiota, and Vaccine Responses

ABSTRACTSubclinical viral infections (SVI), including cytomegalovirus (CMV), are highly prevalent in humans, resulting in lifelong persistence. However, the impact of SVI on the interplay between the host immunity and gut microbiota in the context of environmental exposures is not well defined. We utilized the preclinical nonhuman primate (NHP) model consisting of SVI-free (specific-pathogen-free [SPF]) rhesus macaques and compared them to the animals with SVI (non-SPF) acquired through natural exposure and investigated the impact of SVI on immune cell distribution and function, as well as on gut microbiota. These changes were examined in animals housed in the outdoor environment compared to the controlled indoor environment. We report that SVI are associated with altered immune cell subsets and gut microbiota composition in animals housed in the outdoor environment. Non-SPF animals harbored a higher proportion of potential butyrate-producingFirmicutesand higher numbers of lymphocytes, effector T cells, and cytokine-producing T cells. Surprisingly, these differences diminished following their transfer to the controlled indoor environment, suggesting that non-SPFs had increased responsiveness to environmental exposures. An experimental infection of indoor SPF animals with CMV resulted in an increased abundance of butyrate-producing bacteria, validating that CMV enhanced colonization of butyrate-producing commensals. Finally, non-SPF animals displayed lower antibody responses to influenza vaccination compared to SPF animals. Our data show that subclinical CMV infection heightens host immunity and gut microbiota changes in response to environmental exposures. This may contribute to the heterogeneity in host immune response to vaccines and environmental stimuli at the population level.IMPORTANCEHumans harbor several latent viruses that modulate host immunity and commensal microbiota, thus introducing heterogeneity in their responses to pathogens, vaccines, and environmental exposures. Most of our understanding of the effect of CMV on the immune system is based on studies of children acquiring CMV or of immunocompromised humans with acute or reactivated CMV infection or in ageing individuals. The experimental mouse models are genetically inbred and are completely adapted to the indoor laboratory environment. In contrast, nonhuman primates are genetically outbred and are raised in the outdoor environment. Our study is the first to report the impact of long-term subclinical CMV infection on host immunity and gut microbiota, which is evident only in the outdoor environment but not in the indoor environment. The significance of this study is in highlighting the impact of SVI on enhancing host immune susceptibility to environmental exposures and immune heterogeneity.

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Abstract 14: An Anti-inflammatory Proton Sensing-receptor Contributes To Cardiovascular Protection Of Gut Microbiota-derived Metabolites

Hypertension ◽

10.1161/hyp.78.suppl_1.14 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Liang Xie ◽

Rikeish R Muralitharan ◽

Evany Dinakis ◽

Michael E Nakai ◽

Hamdi Jama ◽

...

Keyword(s):

T Cell ◽

Gut Microbiota ◽

Dietary Fibre ◽

Dietary Intervention ◽

Immune Cell ◽

Ang Ii ◽

Direct Role ◽

Cardiovascular Protection ◽

Anti Inflammatory ◽

The Impact

High fibre (HF) diet protects against hypertension via the production of acidic metabolites, e.g. short-chain fatty acids, by the gut microbiota. While these metabolites have a direct role in blood pressure (BP) regulation, their acidic nature may activate proton-sensing receptors, which have anti-inflammatory functions. G-protein coupled receptor 65 (GPR65) is a proton-sensing receptor activated around pH 6.5 and is critical for gut homeostasis. We hypothesized that GPR65 is involved in the cardiovascular protection by dietary fibre. We first measured cecal pH of C57BL/6 (WT) mice after a 7-day dietary intervention with either HF or low fibre (LF) diets (n=6/group). HF diet lowered cecal pH to a level where GPR65 is highly activated, compared to the LF diet (6.5±0.1 vs 7.6±0.1, P<0.001). The impact of pH and GPR65 on T cell production of IFNγ, a pro-inflammatory cytokine, in vitro was measured by flow cytometry. Acidic pH inhibited the production of IFNγ by CD8+ T cells (pH 6.5 vs pH 7.5, P<0.001). Cells lacking GPR65 had higher IFNγ at both pH (P<0.001). To determine if GPR65 is involved in BP regulation by dietary fibre, WT and GPR65 knockout ( Gpr65 -/- ) mice were implanted with minipumps containing angiotensin II (Ang II, 0.5mg/kg/day, 28 days, n=8-9/group) and fed with HF diet. BP, cardiorenal function and immune cell infiltration were measured. Gpr65 -/- mice had higher BP compared to WT mice after 2 weeks (mean arterial pressure ± SEM; WT 79.8±2.4 vs Gpr65 -/- 95.8±1.6mmHg, P<0.001) and 4 weeks of Ang II infusion (WT 92.3±2.4 vs Gpr65 -/- 99.5±1.3, P=0.062). Gpr65 -/- mice developed cardiac (P=0.035) and renal (P=0.025) hypertrophy, and impaired renal natriuretic (P=0.054) and diuretic (P=0.056) function compared to WT mice. This was accompanied by higher macrophage (P=0.009) and γδ T cell (P=0.014) infiltration in the kidneys. In conclusion, our data suggest that pH-sensing by GPR65 contributes to the protection against hypertension by dietary fibre via inflammatory mechanisms. This is a novel mechanism that contributes to BP regulation via the gut microbiota.

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Peripheral Immunological Cells in Pregnant Women and their Change during Diabetes

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0043-104935 ◽

2017 ◽

Vol 125 (10) ◽

pp. 677-683 ◽

Cited By ~ 1

Author(s):

Ulrike Friebe-Hoffmann ◽

Linda Antony ◽

Jan-Steffen Kruessel ◽

Brigitte Pawlowski ◽

Thomas Hoffmann

Keyword(s):

T Cells ◽

Gestational Diabetes ◽

Pregnant Women ◽

Immune Cell ◽

Γδ T Cells ◽

Complication Rates ◽

And Shifts ◽

The Impact ◽

Pregnant Diabetic

AbstractDuring the last decades the incidence of diabetes has dramatically increased as well as the number of pregnant diabetic women. There is still missing data regarding patterns and shifts of immune cell populations due to pregnancy with or without diabetes. The study aimed to investigate the impact of pregnancy, type 1 diabetes (T1D) and gestational diabetes mellitus (GDM) on different immune cells in female. The number and proportion of CD3-, CD4-, CD8- and γδ T-cells as well as B-, NK-, NKT- and dendritic cells (DC) incl. rate of apoptosis was analyzed in peripheral blood samples from 24 non-pregnant women, 24 pregnant controls, 25 non-pregnant T1D, 18 women with GDM and 15 pregnant T1D (PT1D) women. Compared to healthy controls, healthy pregnant women had reduced numbers of lymphoid DC and γδ T-cells, while women with gestational diabetes presented with increased numbers of γδ T-cells. Pregnant women with T1D showed increased NKT cells and a decrease of NK cells compared to healthy pregnant or non-pregnant T1D women. Apoptosis of γδ T-cells in healthy pregnant women was found to be decreased in comparison to their non-pregnant controls while apoptosis of myeloid and lymphoid DC was increased in pregnant T1D in comparison to non-pregnant T1D. Those results may indicate that increased complication rates during diabetic pregnancies might be due to an impaired adaptation of the immune system.

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B cell, CD8+ T cell and gamma delta T cell infiltration alters alveolar immune cell homeostasis in HIV-infected Malawian adults

Wellcome Open Research ◽

10.12688/wellcomeopenres.12869.3 ◽

2018 ◽

Vol 2 ◽

pp. 105 ◽

Cited By ~ 3

Author(s):

Andrew Mwale ◽

Annemarie Hummel ◽

Leonard Mvaya ◽

Raphael Kamng'ona ◽

Elizabeth Chimbayo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hiv Infection ◽

Immune Cell ◽

Cell Populations ◽

Monocyte Subset ◽

Gamma Delta ◽

Cell Homeostasis ◽

Tract Infections ◽

The Impact

Background: HIV infection is associated with increased risk to lower respiratory tract infections (LRTI). However, the impact of HIV infection on immune cell populations in the lung is not well defined. We sought to comprehensively characterise the impact of HIV infection on immune cell populations in the lung. Methods: Twenty HIV-uninfected controls and 17 HIV-1 infected ART-naïve adults were recruited from Queen Elizabeth Central Hospital, Malawi. Immunophenotyping of lymphocyte and myeloid cell populations was done on bronchoalveolar lavage fluid and peripheral blood cells. Results: We found that the numbers of CD8 + T cells, B cells and gamma delta T cells were higher in BAL fluid of HIV-infected adults compared to HIV-uninfected controls (all p<0.05). In contrast, there was no difference in the numbers of alveolar CD4 + T cells in HIV-infected adults compared to HIV-uninfected controls (p=0.7065). Intermediate monocytes were the predominant monocyte subset in BAL fluid (HIV-, 63%; HIV+ 81%), while the numbers of classical monocytes was lower in HIV-infected individuals compared to HIV-uninfected adults (1 × 10 5 vs. 2.8 × 10 5 cells/100ml of BAL fluid, p=0.0001). The proportions of alveolar macrophages and myeloid dendritic cells was lower in HIV-infected adults compared to HIV-uninfected controls (all p<0.05). Conclusions: Chronic HIV infection is associated with broad alteration of immune cell populations in the lung, but does not lead to massive depletion of alveolar CD4 + T cells. Disruption of alveolar immune cell homeostasis likely explains in part the susceptibility for LRTIs in HIV-infected adults.

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Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model

Gut ◽

10.1136/gutjnl-2018-317431 ◽

2019 ◽

Vol 69 (2) ◽

pp. 283-294 ◽

Cited By ~ 32

Author(s):

Min-Soo Kim ◽

Yoonhee Kim ◽

Hyunjung Choi ◽

Woojin Kim ◽

Sumyung Park ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Neurofibrillary Tangles ◽

Immune Cell ◽

Amyloid Β ◽

Memory Deficits ◽

Faecal Microbiota ◽

Inflammatory Monocytes ◽

The Impact

ObjectiveCerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive.DesignUsing a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.ResultsComposition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice.ConclusionThese results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

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Differential immune cell infiltrations between healthy periodontal and chronic periodontitis tissues

BMC Oral Health ◽

10.1186/s12903-020-01287-0 ◽

2020 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Wei Li ◽

Zheng Zhang ◽

Zuo-min Wang

Keyword(s):

T Cells ◽

B Cells ◽

Mast Cells ◽

Plasma Cells ◽

Immune Cell ◽

Memory T Cells ◽

Host Immunity ◽

Memory B Cells ◽

Helper T Cells ◽

Follicular Helper

Abstract Background Host immunity plays an important role against oral microorganisms in periodontitis. Methods This study assessed the infiltrating immune cell subtypes in 133 healthy periodontal and 210 chronic periodontitis tissues from Gene Expression Omnibus (GEO) datasets using the CIBERSORT gene signature files. Results Plasma cells, naive B cells and neutrophils were all elevated in periodontitis tissues, when compared to those in healthy controls. In contrast, memory B cells, resting dendritic, mast cells and CD4 memory cells, as well as activated mast cells, M1 and M2 macrophages, and follicular helper T cells, were mainly present in healthy periodontal tissues. Furthermore, these periodontitis tissues generally contained a higher proportion of activated CD4 memory T cells, while the other subtypes of T cells, including resting CD4 memory T cells, CD8 T cells, follicular helper T cells (TFH) and regulatory T cells (Tregs), were relatively lower in periodontitis tissues, when compared to healthy tissues. The ratio of dendritic and mast cells and macrophages was lower in periodontitis tissues, when compared to healthy tissues. In addition, there was a significant negative association of plasma cells with most of the other immune cells, such as plasma cells vs. memory B cells (γ = − 0.84), plasma cells vs. resting dendritic cells (γ = − 0.64), plasma cells vs. resting CD4 memory T cells (γ = 0.50), plasma cells versus activated dendritic cells (γ = − 0.46), plasma cells versus TFH (γ = − 0.46), plasma cells versus macrophage M2 cells (γ = − 0.43), or plasma cells versus macrophage M1 cells (γ = − 0.40), between healthy control and periodontitis tissues. Conclusion Plasma cells, naive B cells and neutrophils were all elevated in periodontitis tissues. The infiltration of different immune cell subtypes in the periodontitis site could lead the host immunity against periodontitis.

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Tumor Size Matters—Understanding Concomitant Tumor Immunity in the Context of Hypofractionated Radiotherapy with Immunotherapy

Cancers ◽

10.3390/cancers12030714 ◽

2020 ◽

Vol 12 (3) ◽

pp. 714

Author(s):

Jean Philippe Nesseler ◽

Mi-Heon Lee ◽

Christine Nguyen ◽

Anusha Kalbasi ◽

James W. Sayre ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Immune Cell ◽

Tumor Regression ◽

Experimental Models ◽

Tumor Burden ◽

Local Regression ◽

Cell Content ◽

Primary Tumors ◽

The Impact

The purpose of this study was to determine the dynamic contributions of different immune cell subsets to primary and abscopal tumor regression after hypofractionated radiation therapy (hRT) and the impact of anti-PD-1 therapy. A bilateral syngeneic FSA1 fibrosarcoma model was used in immunocompetent C3H mice, with delayed inoculation to mimic primary and microscopic disease. The effect of tumor burden on intratumoral and splenic immune cell content was delineated as a prelude to hRT on macroscopic T1 tumors with 3 fractions of 8 Gy while microscopic T2 tumors were left untreated. This was performed with and without systemic anti-PD-1. Immune profiles within T1 and T2 tumors and in spleen changed drastically with tumor burden in untreated mice with infiltrating CD4+ content declining, while the proportion of CD4+ Tregs rose. Myeloid cell representation escalated in larger tumors, resulting in major decreases in the lymphoid:myeloid ratios. In general, activation of Tregs and myeloid-derived suppressor cells allow immunogenic tumors to grow, although their relative contributions change with time. The evidence suggests that primary T1 tumors self-regulate their immune content depending on their size and this can influence the lymphoid compartment of T2 tumors, especially with respect to Tregs. Tumor burden is a major confounding factor in immune analysis that has to be taken into consideration in experimental models and in the clinic. hRT caused complete local regression of primary tumors, which was accompanied by heavy infiltration of CD8+ T cells activated to express IFN-γ and PD-1; while certain myeloid populations diminished. In spite of this active infiltrate, primary hRT failed to generate the systemic conditions required to cause abscopal regression of unirradiated microscopic tumors unless PD-1 blockade, which on its own was ineffective, was added to the RT regimen. The combination further increased local and systemically activated CD8+ T cells, but few other changes. This study emphasizes the subtle interplay between the immune system and tumors as they grow and how difficult it is for local RT, which can generate a local immune response that may help with primary tumor regression, to overcome the systemic barriers that are generated so as to effect immune regression of even small abscopal lesions.

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Effect of TCHL-based therapy on immune cell content in on-treatment, neoadjuvant-treated HER2-positive breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.583 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 583-583

Author(s):

Niamh M. Keegan ◽

Sinead Toomey ◽

Joanna Fay ◽

Stephen F. Madden ◽

Bruce Moran ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Immune Cell ◽

Cell Populations ◽

Breast Cancer Patients ◽

Myeloid Dendritic Cells ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

The Impact ◽

Positive Breast Cancer

583 Background: In the TCHL trial (NCT01485926) 78 women with HER2-positive breast cancer (BC) underwent neo-adjuvant treatment with either TCH (Docetaxel, Carboplatin, Trastuzumab) or TCHL (TCH + Lapatinib) therapy. Of the 78 patients, 24 consented to an optional on-treatment biopsy 20 days after 1 cycle of therapy. We analysed the impact of tumour infiltrating lymphocytes (TILs) on pathological complete response (pCR) and also determined the impact of TCH/TCHL therapy on immune cell modulation after 20 days of treatment. Methods: We assessed TIL and stromal lymphocytes (SL) counts using immunohistochemical staining with Haemotoxalyin+Eosin, AE1/AE3 and CD45 in formalin fixed paraffin embedded (FFPE) baseline biopsy samples and in fresh frozen (FF) biopsies taken 20-days post cycle 1 (Day-20) of TCH/TCHL. RNA libraries were generated, using the Truseq mRNA library prep kit on the Neoprep platform and sequenced on the NextSeq 500. We measured the transcriptomic profile of 8 pre and on-treatment sample pairs and then used the Microenvironment Cell Populations (MCP)-counter method to measure the abundance of 10 immune cell populations (T cells, CD8 T cells, cytotoxic lymphocytes, NK cells, B lineage, myeloid dendritic cells, neutrophils, endothelial cells and fibroblasts). Results: We found that higher baseline levels of TILs (p = 0.045) but not SL were associated with an increased likelihood of a patient achieving a pCR to TCH/L based therapy. We found in day 20 on-treatment biopsies of women that subsequently went onto have a pCR that levels of SLs but not TILs were significantly higher (p = 0.049) than in those women who did not have a pCR. Finally we found significant increases in the level of monocytes (p = 0.05) and fibroblasts (p = 0.01), but not other immune cell populations, in the day 20 on-treatment biopsies in comparison with the mutated pre-treatment biopsies. Conclusions: In our study baseline TILs but not SLs have a predictive role in the likelihood of a patient achieving a pCR. We also found that TCHL based therapy significantly altered both monocytes and fibroblasts, indicating a possible role for these immune subtypes in response to TCHL therapy.

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RvE1 Impacts the Gingival Inflammatory Infiltrate by Inhibiting the T Cell Response in Experimental Periodontitis

Frontiers in Immunology ◽

10.3389/fimmu.2021.664756 ◽

2021 ◽

Vol 12 ◽

Author(s):

Carla Alvarez ◽

Henrique Abdalla ◽

Salwa Sulliman ◽

Paola Rojas ◽

Yu-Chiao Wu ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Inflammatory Infiltrate ◽

Alveolar Bone ◽

Immune Cell ◽

Therapeutic Potential ◽

T Cell Response ◽

Cervical Lymph Nodes ◽

Wide Range ◽

The Impact

Periodontitis is a chronic inflammatory disease associated with the formation of dysbiotic plaque biofilms and characterized by the progressive destruction of the alveolar bone. The transition from health to disease is characterized by a shift in periodontal immune cell composition, from mostly innate (neutrophils) to adaptive (T lymphocytes) immune responses. Resolvin E1 (RvE1) is a specialized pro-resolution mediator (SPMs), produced in response to inflammation, to enhance its resolution. Previous studies have indicated the therapeutic potential of RvE1 in periodontal disease; however, the impact of RvE1 in the microbial-elicited osteoclastogenic immune response remains uncharacterized in vivo. In the present study, we studied the impact of RvE1 on the gingival inflammatory infiltrate formation during periodontitis in a mouse model. First, we characterized the temporal-dependent changes of the main immune cells infiltrating the gingiva by flow cytometry. Then, we evaluated the impact of early or delayed RvE1 administration on the gingival immune infiltration and cervical lymph nodes composition. We observed a consistent inhibitory outcome on T cells -particularly effector T cells- and a protective effect on regulatory T cells (Tregs). Our data further demonstrated the wide range of actions of RvE1, its preventive role in the establishment of the adaptive immune response during inflammation, and bone protective capacity.

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Flow Cytometric Analysis Revealed a Significant Accumulation of Terminally Differentiated T cell Subtypes in the Circulating Lymphocytes of Cytomegalovirus (CMV) Positive Follicular Lymphoma Patients

10.47363/jcbr/2021(3)132 ◽

2021 ◽

pp. 1-9

Author(s):

Lugos MD ◽

◽

Dangana A ◽

Ntuhun BD ◽

Oluwatayo BO ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Follicular Lymphoma ◽

B Cell ◽

Flow Cytometric Analysis ◽

B Cell Lymphoma ◽

T Cell Subsets ◽

Cmv Infection ◽

Flow Cytometric ◽

The Impact

Follicular lymphoma (FL), a non-Hodgkin lymphoma, is an indolent cancer of the B cell lineage that runs a chronic deterioration course that can result in multiple treatment episodes leading to resistance and possible transformation to diffuse large B cell lymphoma. Cytomegalovirus (CMV) reactivation during chemotherapy or after an organ or hematopoietic stem cell transplantation is a major cause of morbidity and mortality. This study tests the hypothesis that some of the heterogeneity of FL might result from chronic infection with Cytomegalovirus (CMV). This research was intended to appraise the impact of CMV infection on the subtypes of T cells in follicular lymphoma patients. We accessed stored peripheral blood mononuclear cells (PMBCs) from patients of known CMV serostatus recruited into an FL clinical trial. We undertook a multicolour flow cytometric analysis of the PBMCs and compared the number of lymphocyte subtypes of CMV-positive and CMV-negative FL patients. Data showed a significant increase in the quantity of terminally differentiated (TEMRA) T cell subsets, including EM3-CD8 (P=0.005), EM3-CD4 (P=0.018), E-CD4 (P=0.029), E-CD8 (P=0.033) and pE2-CD4 (P=0.046) phenotypes, as well as increased NKT cells (P=0.031) among CMV-positive patients compared to the negative group. Our findings support the hypothesis that recurrent infections characterise CMV infection in FL due to accelerated immune senescence and the accumulation of exhausted T cells. Based on the data, a case could be argued for the routine application of CMV screening in FL before treatment with chemo-immunotherapy to implement enhanced infection surveillance in CMV-positive patients. These discoveries can eventually help improve the treatment approaches in the management of FL toward a combinatorial viewpoint for direct cytotoxic and indirect immunomodulatory outlook

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DNA-scaffolded biomaterials enable modular and tunable control of cell-based cancer immunotherapies

10.1101/587105 ◽

2019 ◽

Cited By ~ 3

Author(s):

Xiao Huang ◽

Jasper Z. Williams ◽

Ryan Chang ◽

Zhongbo Li ◽

Eric Gai ◽

...

Keyword(s):

T Cells ◽

Immune Cell ◽

Ex Vivo ◽

Cell Activity ◽

Engineered T Cells ◽

Advanced Biomaterials ◽

Cancer Immunotherapies ◽

Biodegradable Particles ◽

The Impact

Advanced biomaterials provide versatile ways to spatially and temporally control immune cell activity, potentially enhancing their therapeutic potency and safety. Precise cell modulation demands multi-modal display of functional proteins with controlled densities on biomaterials. Here, we develop an artificial immune cell engager (AICE) platform – biodegradable particles onto which multiple proteins are densely loaded with ratiometric control via short nucleic acid tethers. We demonstrate the impact of AICE with varying ratios of anti-CD3 and anti-CD28 antibodies onex vivoexpansion of human primary T cells. We also show that AICE can be used to control the activity of engineered T cellsin vivo. AICE injected intratumorally can provide a local priming signal for systemically administered AND-gate chimeric antigen receptor T cells, driving local tumor clearance while sparing uninjected tumors that model potentially cross-reactive healthy tissues. This modularly functionalized biomaterial thus provides a flexible platform to achieve sophisticated control over cell-based immunotherapies.

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