scholarly journals LN Monocytes Limit DC-Poly I:C Induced Cytotoxic T Cell Response via IL-10 and Induction of Suppressor CD4 T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Anita Tewari ◽  
Miglena G. Prabagar ◽  
Sophie L. Gibbings ◽  
Kavita Rawat ◽  
Claudia V. Jakubzick
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Cytotoxic T Cells ◽  
T Cell Response ◽  
Poly I:C ◽  
Cytotoxic T Cell ◽  
Melanoma Model ◽  
Important Addition

Every immune response has accelerators and brakes. Depending on the pathogen or injury, monocytes can play either role, promoting or resolving immunity. Poly I:C, a potent TLR3 ligand, licenses cross-presenting dendritic cells (DC1) to accelerate a robust cytotoxic T cells response against a foreign antigen. Poly I:C thus has promise as an adjuvant in cancer immunotherapy and viral subunit vaccines. Like DC1s, monocytes are also abundant in the LNs. They may act as either immune accelerators or brakes, depending on the inflammatory mediator they encounter. However, little is known about their contribution to adaptive immunity in the context of antigen and Poly I:C. Using monocyte-deficient and chimeric mice, we demonstrate that LN monocytes indirectly dampen a Poly I:C induced antigen-specific cytotoxic T cell response, exerting a “braking” function. This effect is mediated by IL-10 production and induction of suppressor CD4+ T cells. In a metastatic melanoma model, we show that a triple-combination prophylactic treatment consisting of anti-IL-10, tumor peptides and Poly I:C works because removing IL-10 counteracts the monocytic brake, resulting in significantly fewer tumors compared to mice treated with tumor peptides and Poly I:C alone. Finally, in human LN tissue, we observed that monocytes (unlike DCs) express high levels of IL-10, suggesting that anti-IL-10 may be an important addition to treatments. Overall, our data demonstrates that LN monocytes regulate the induction of a robust DC1-mediated immune response. Neutralization of either IL-10 or monocytes can augment Poly I:C-based treatments and enhance T cell cytotoxicity.

scholarly journals Role of viral infectivity in the induction of influenza virus-specific cytotoxic T cells.

1978 ◽  
Vol 147 (4) ◽  
pp. 1236-1252 ◽  
Author(s):  
T J Braciale ◽  
K L Yap
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Response ◽  
Infectious Virus ◽  
Cytotoxic T Cells ◽  
T Cell Response ◽  
Cytotoxic T Cell

This report examines the requirement for infectious virus in the induction of influenza virus-specific cytotoxic T cells. Infectious influenza virus was found to be highly efficient at generating both primary and secondary cytotoxic T-cell response in vivo. Inactivated influenza virus however, failed to stimulate a detectable cytotoxic T-cell response in vivo even at immunizing doses 10(5)-10(6)-fold higher than the minimum stimulatory dose of infectious virus. Likewise inactivated virus failed to sensitize target cells for T cell-mediated lysis in vitro but could stimulate a specific cytotoxic response from primed cells in vitro. Possible requirements for the induction of virus-specific cytotoxic T-cell responses are discussed in light of these observations and those of other investigators.

scholarly journals Neoantigen-specific CD4+ T-cell response is critical for the therapeutic efficacy of cryo-thermal therapy

2020 ◽  
Vol 8 (2) ◽  
pp. e000421
Author(s):  
Peng Peng ◽  
Hongming Hu ◽  
Ping Liu ◽  
Lisa X Xu
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Antigen ◽  
Cell Response ◽  
Antitumor Immunity ◽  
T Cell Response ◽  
Thermal Therapy ◽  
Term Survival

BackgroundTraditional tumor thermal ablations, such as radiofrequency ablation (RFA) and cryoablation, can result in good local control of tumor, but traditional tumor thermal ablations are limited by poor long-term survival due to the failure of control of distal metastasis. Our previous studies developed a novel cryo-thermal therapy to treat the B16F10 melanoma mouse model. Long-term survival and T-cell-mediated durable antitumor immunity were achieved after cryo-thermal therapy, but whether tumor antigen-specific T-cells were augmented by cryo-thermal therapy was not determined.MethodsThe long-term antitumor therapeutic efficacy of cryo-thermal therapy was performed in B16F10 murine melanoma models. Splenocytes derived from mice treated with RFA or cryo-thermal therapy were coincubated with tumor antigen peptides to detect the frequency of antigen specific CD4+ and CD8+ T-cells by flow cytometry. Splenocytes were then stimulated and expanded by αCD3 or peptides and adoptive T-cell therapy experiments were performed to identify the antitumor efficacy of T-cells induced by RFA and cryo-thermal therapy. Naïve mice and tumor-bearing mice were used as control groups.ResultsLocal cryo-thermal therapy generated a stronger systematic antitumor immune response than RFA and a long-lasting antitumor immunity that protected against tumor rechallenge. In vitro studies showed that the antigen-specific CD8+ T-cell response was induced by both cryo-thermal therapy and RFA, but the strong neoantigen-specific CD4+ T-cell response was only induced by cryo-thermal therapy. Cryo-thermal therapy-induced strong antitumor immune response was mainly mediated by CD4+ T-cells, particularly neoantigen-specific CD4+ T-cells.ConclusionCryo-thermal therapy induced a stronger and broader antigen-specific memory T-cells. Specifically, cryo-thermal therapy, but not RFA, led to a strong neoantigen-specific CD4+ T-cell response that mediated the resistance to tumor challenge.

scholarly journals The Polyomavirus BK Large T-Antigen-Derived Peptide Elicits an HLA-DR Promiscuous and Polyfunctional CD4+T-Cell Response

2011 ◽  
Vol 18 (5) ◽  
pp. 815-824 ◽  
Author(s):  
Bala Ramaswami ◽  
Iulia Popescu ◽  
Camila Macedo ◽  
Chunqing Luo ◽  
Ron Shapiro ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Antigen ◽  
T Cell Response ◽  
Peptide Sequence ◽  
Large T Antigen ◽  
Hla Dr ◽  
Ifn Γ

ABSTRACTBK virus (BKV) nephropathy and hemorrhagic cystitis are increasingly recognized causes of disease in renal and hematopoietic stem cell transplant recipients, respectively. Functional characterization of the immune response to BKV is important for clinical diagnosis, prognosis, and vaccine design. A peptide mix (PepMix) and overlapping (OPP) or random (RPP) peptide pools derived from BKV large T antigen (LTA) were used to restimulate 14-day-expanded peripheral blood mononuclear cells (PBMC) from 27 healthy control subjects in gamma interferon (IFN-γ)-specific enzyme-linked immunospot (ELISPOT) assays. A T-cell response to LTA PepMix was detected in 15/27 subjects. A response was frequently observed with peptides derived from the helicase domain (9/15 subjects), while the DNA binding and host range domains were immunologically inert (0/15 subjects). For all nine subjects who responded to LTA peptide pools, the immune response could be explained largely by a 15-mer peptide designated P313. P313-specific CD4+T-cell clones demonstrated (i) stringent LTA peptide specificity; (ii) promiscuous recognition in the context of HLA-DR alleles; (iii) cross recognition of homologous peptides from the polyomavirus simian virus 40 (SV40); (iv) an effector memory phenotype, CD107a expression, and intracellular production of IFN-γ and tumor necrosis factor alpha (TNF-α); (v) cytotoxic activity in a chromium release assay; and (vi) the ability to directly present cognate antigen to autologous T cells. In conclusion, T-cell-mediated immunity to BKV in healthy subjects is associated with a polyfunctional population of CD4+T cells with dual T-helper and T-cytotoxic properties. HLA class II promiscuity in antigen presentation makes the targeted LTA peptide sequence a suitable candidate for inclusion in immunotherapy protocols.

scholarly journals Race between Retroviral Spread and CD4+ T-Cell Response Determines the Outcome of Acute Friend Virus Infection

2009 ◽  
Vol 83 (21) ◽  
pp. 11211-11222 ◽  
Author(s):  
Rebecca Pike ◽  
Andrew Filby ◽  
Mickaël J.-Y. Ploquin ◽  
Urszula Eksmond ◽  
Rute Marques ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Acute Infection ◽  
T Cell Response ◽  
Friend Virus ◽  
Antiviral Immune Response ◽  
Ultimate Failure ◽  
Necessary And Sufficient

ABSTRACT Retroviruses can establish persistent infection despite induction of a multipartite antiviral immune response. Whether collective failure of all parts of the immune response or selective deficiency in one crucial part underlies the inability of the host to clear retroviral infections is currently uncertain. We examine here the contribution of virus-specific CD4+ T cells in resistance against Friend virus (FV) infection in the murine host. We show that the magnitude and duration of the FV-specific CD4+ T-cell response is directly proportional to resistance against acute FV infection and subsequent disease. Notably, significant protection against FV-induced disease is afforded by FV-specific CD4+ T cells in the absence of a virus-specific CD8+ T-cell or B-cell response. Enhanced spread of FV infection in hosts with increased genetic susceptibility or coinfection with Lactate dehydrogenase-elevating virus (LDV) causes a proportional increase in the number of FV-specific CD4+ T cells required to control FV-induced disease. Furthermore, ultimate failure of FV/LDV coinfected hosts to control FV-induced disease is accompanied by accelerated contraction of the FV-specific CD4+ T-cell response. Conversely, an increased frequency or continuous supply of FV-specific CD4+ T cells is both necessary and sufficient to effectively contain acute infection and prevent disease, even in the presence of coinfection. Thus, these results suggest that FV-specific CD4+ T cells provide significant direct protection against acute FV infection, the extent of which critically depends on the ratio of FV-infected cells to FV-specific CD4+ T cells.

EBV-positive lymphoma patients have a selective deficiency in EBV immunity

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21032-21032
Author(s):  
K. N. Heller ◽  
P. G. Steinherz ◽  
C. S. Portlock ◽  
C. Münz
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Healthy Volunteers ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Specific Immune Response ◽  
Cell Responses

21032 Background: Epstein-Barr virus (EBV) asymptomatically establishes persistent infections in more than 90% of the adult population. However, due to effective immune control, only a minority of infected carriers develops spontaneous EBV-associated lymphomas. Since EBV nuclear antigen-1 (EBNA1) is the only protein expressed in all proliferating EBV infected cells we hypothesize that EBNA1 specific immune response is critical in preventing EBV-positive lymphomas. Methods: After informed consent, peripheral blood from healthy volunteers and lymphoma patients (prior to therapy- no evidence of cytopenia) were stimulated (ex vivo) with overlapping peptides covering the immunogenic EBNA1 (aa400–641) sequence. Frequency of EBNA1-specific T-cells were assessed by intracellular cytokine staining and flow cytometric proliferation assays. Cytokine pattern, surface marker phenotype and functional reactivity against EBV specific and control antigens were analyzed. Results: Patient and volunteer immune responses to control antigens and other viruses were assessed and statistically indistinguishable. EBNA1 specific CD4+ T cell responses were detected among 18 of 20 healthy carriers, and among 10 of 16 patients with EBV-negative lymphoma (relative to healthy volunteers p=0.145 via paired student T test). None of the patients with EBV-positive lymphomas (n=8) had a detectable EBNA1-specific CD4+ T-cell response (p<0.003 relative to healthy volunteers and patients with EBV-negative lymphomas). Conclusions: Healthy volunteers and patients with EBV-negative lymphoma have statistically similar EBNA1-specific CD4+ T cell responses. Although patients with EBV-positive lymphoma have intact immune responses to common viruses and antigens, they selectively lack an EBNA1-specific CD4+ T cell response. An intact EBNA1 specific immune response among patients with EBV-negaitve lymphoma implies that lymphoma is not a cause of a selective immune deficiency. On the contrary, these findings suggest that EBNA1-specific CD4+ T cells are critical in the prevention of EBV mediated lymphomas, and a defect in EBNA1 specific immunity may leave EBV carriers suseptible to EBV-positive lymphomas. EBNA1- specific CD4+ T cell function may be a new target for therapies of EBV-associated malignancies. No significant financial relationships to disclose.

scholarly journals The T cell receptor repertoire reflects the dynamics of the immune response to vaccination

2021 ◽  
Author(s):  
Kevin Mohammed ◽  
Austin Meadows ◽  
Sandra Hatem ◽  
Viviana Simon ◽  
Anitha D Jayaprakash ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Influenza Vaccine ◽  
T Cell Receptor ◽  
Cell Response ◽  
Cell Receptor ◽  
Physical Symptoms ◽  
T Cell Response ◽  
Tcr Repertoire

Early, high-resolution metrics are needed to ascertain the immune response to vaccinations. The T cell receptor (TCR), a heterodimer of one α and one β chain, is a promising target, with the complete TCR repertoire reflecting the T cells present in an individual. To this end, we developed Tseek, an unbiased and accurate method for profiling the TCR repertoire by sequencing the TCR α and β chains and developing a suite of tools for repertoire analysis. An added advantage is the ability to non-invasively analyze T cells in peripheral blood mononuclear cells (PBMCs). Tseek and the analytical suite were used to explore the T cell response to both the COVID-19 mRNA vaccine (n=9) and the seasonal inactivated Influenza vaccine (n=5) at several time points. Neutralizing antibody titers were also measured in the covid vaccine samples. The COVID-19 vaccine elicited a broad T cell response involving multiple expanded clones, whereas the Influenza vaccine elicited a narrower response involving fewer clones. Many distinct T cell clones responded at each time point, over a month, providing temporal details lacking in the antibody measurements, especially before the antibodies are detectable. In individuals recovered from a SARS-CoV-2 infection, the first vaccine dose elicited a robust T cell response, while the second dose elicited a comparatively weaker response, indicating a saturation of the response. The physical symptoms experienced by the recipients immediately following the vaccinations were not indicative of the TCR/antibody responses, while a weak TCR response seemed to presage a weak antibody response. We also found that the TCR repertoire acts as an individual fingerprint: donors of blood samples taken years apart could be identified solely based upon their TCR repertoire, hinting at other surprising uses the TCR repertoire may have. These results demonstrate the promise of TCR repertoire sequencing as an early and sensitive measure of the adaptive immune response to vaccination, which can help improve immunogen selection and optimize vaccine dosage and spacing between doses.

scholarly journals Reduced Expression of Autophagy Markers and Expansion of Myeloid-Derived Suppressor Cells Correlate With Poor T Cell Response in Severe COVID-19 Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Sergej Tomić ◽  
Jelena Đokić ◽  
Dejan Stevanović ◽  
Nataša Ilić ◽  
Alisa Gruden-Movsesijan ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cell Response ◽  
Suppressor Cells ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Myeloid Derived Suppressor Cells ◽  
Immunological Mechanisms

Widespread coronavirus disease (COVID)-19 is causing pneumonia, respiratory and multiorgan failure in susceptible individuals. Dysregulated immune response marks severe COVID-19, but the immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, which is hampering the development of efficient treatments. Here we analyzed ~140 parameters of cellular and humoral immune response in peripheral blood of 41 COVID-19 patients and 16 age/gender-matched healthy donors by flow-cytometry, quantitative PCR, western blot and ELISA, followed by integrated correlation analyses with ~30 common clinical and laboratory parameters. We found that lymphocytopenia in severe COVID-19 patients (n=20) strongly affects T, NK and NKT cells, but not B cells and antibody production. Unlike increased activation of ICOS-1+ CD4+ T cells in mild COVID-19 patients (n=21), T cells in severe patients showed impaired activation, low IFN-γ production and high functional exhaustion, which correlated with significantly down-regulated HLA-DR expression in monocytes, dendritic cells and B cells. The latter phenomenon was followed by lower interferon responsive factor (IRF)-8 and autophagy-related genes expressions, and the expansion of myeloid derived suppressor cells (MDSC). Intriguingly, PD-L1-, ILT-3-, and IDO-1-expressing monocytic MDSC were the dominant producers of IL-6 and IL-10, which correlated with the increased inflammation and accumulation of regulatory B and T cell subsets in severe COVID-19 patients. Overall, down-regulated IRF-8 and autophagy-related genes expression, and the expansion of MDSC subsets could play critical roles in dysregulating T cell response in COVID-19, which could have large implications in diagnostics and design of novel therapeutics for this disease.

Transfection of Dendritic Cells with In Vitro Transcribed RNA Induces Polyclonal CMV-Specific CD8+ and CD4+ Mediated T Cell Responses.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1354-1354
Author(s):  
Annkristin Heine ◽  
Tobias Holderried ◽  
Frank Grünebach ◽  
Silke Appel ◽  
Markus M. Weck ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Response ◽  
Cytotoxic T Cells ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
Rna Transfection

Abstract Transfection of dendritic cells (DC) with in vitro transcribed RNA was shown to be a highly efficient method to generate antigen specific T cells, probably due to the induction of a polyclonal T cell response directed against multiple antigens presented on different HLA allels. However, the experimental evidence of this assumption remains to be demonstrated. To accomplish this, we used monocyte derived DC that were electroporated with RNA coding for the CMV pp65 antigen. The induction and expansion of antigen specific CD8+ and CD4+ T cells was assessed using a pannel of peptides derived from this antigen and presented on HLA-A2, -A1, -A11, -A24, -B35 and -B7 in IFN-g ELISPOT, 51Cr-release and proliferation assays. Autologous DC generated from CMV positive healthy donors were pulsed with peptides or transfected with pp65 RNA and utilized as stimulators. Autologous purified CD8+ and CD4+ lymphocytes were used as effector cells. By applying this approach we found that transfection of DC with pp65 RNA induces an expansion of polyclonal CD8+ mediated T cell responses that recognized peptide antigens presented on different HLA molecules. These in vitro generated cytotoxic T cells were able to efficiently lyse DC pulsed with pp65 derived peptides or transfected with the cognate RNA in an antigen specific manner after several in vitro restimulations. Furthermore, this experimental approach allowed the identification of the immunodominace of T cell epitopes presented upon RNA transfection. The HLA-2 directed responses were more pronounced as compared to the HLA-A1, -A11, -A24 or -B35 allels. In contrast, in 7 out of 7 HLA-A2 and HLA-B7 positive donors B7-peptides elicited a stronger T cell response than the A2-peptide, indicating the immunodominance of HLA-B7 epitopes. Interestingly, transfection of DC with pp65 RNA resulted in the induction of CD4+ antigen specific T cells that produced IFN-g and proliferated upon stimulation with transfected DC. In the next set of experiments we analyzed the possible induction of CMV specific T cells that recognize epitopes deduced from different antigens. Co-transfection of DC with a mixture of RNAs coding for the CMV pp65 and IE1 antigens elicited polyclonal T lymphocytes specific for peptides derived from both antigens. More importantly, polyclonal cytotoxic T cells could be elicited in peripheral blood of 2 out of 3 CMV negative donors demonstrating the efficiency of this approach. Our results demonstrate that DC transfected with RNA can elicit polyclonal T cell responses and have implications for the development of immunotherapeutic strategies to target viral or tumor associated antigens.

Increased Cytotoxic T-Cell Infiltrates in the Bone Marrow Is an Independent Adverse Prognostic Factor in Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1492-1492
Author(s):  
Grzegorz S. Nowakowski ◽  
Chin-Yang Li ◽  
David Dingli ◽  
Shaji Kumar ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Immune Response ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Prognostic Factor ◽  
Cytotoxic T Cells ◽  
Cytotoxic T Cell ◽  
Newly Diagnosed

Abstract Background: Cytotoxic T-cell infiltrates are a nearly universal finding in the bone marrow of patients with multiple myeloma. It has been postulated that presence of T-cells in the bone marrow of multiple myeloma (MM) patients represents an immune response against the tumor and therefore, might be associated with an improved prognosis. However, the impact of bone marrow T-cells on the prognosis of multiple myeloma patients has not been studied systematically. Methods: Bone marrow biopsies of patients with newly diagnosed multiple myeloma were stained by immnohistochemistry for the CD8 antigen and reviewed by a blinded hematopathologist. Three high power fields are reviewed for each biopsy and the total number of CD8 positive cells counted and reported. For patients with more than 300 cells per 3 fields, results were reported as &gt;300. The number of bone marrow CD8 positive cells was then correlated with patients’ clinical data, including other prognostic factors and overall survival. Results: Bone marrow biopsy specimens from 100 patients, performed within the week of a diagnosis of multiple myeloma and collected between May 1998 and January 2001 were evaluated. The median number of CD8 positive cells was 270 (33 – &gt;300). Patients’ characteristics are shown in Table 1. Median follow up was 30 months (0–80). The number of cytotoxic T-cells as a continuous variable was a risk factor for shortened overall survival, HR 1.86 (95% CI 1.11–3.35). Using minimal p value approach, the cutoff of 270 cells (the median) risk stratified patients into two groups: the median survival of patients with &gt; 270 CD8 positive cells was 16 months vs. 48 months in patients with ≤270 cells, p=0.005 (Figure). In multivariate analysis including age, B2M, albumin, CRP, bone marrow plasma cell percentage and plasma cell labeling index, the number of cytotoxic T-cells was an independent predictor of overall survival was HR 3.1, p=0.0017. Conclusion: We show that the number of cytotoxic T-cells in the bone marrow is a strong and independent prognostic factor in patients with newly diagnosed multiple myeloma. Our observation does not contradict the hypothesis that cytotoxic T-cells participate in an immune response against the tumor since our findings may represent a higher level of immune response associated with baseline aggressive disease biology. However, our study suggests for the first time that increased marrow cytotoxic T-cells have an adverse effect on outcome in myeloma, and suggest that these cells may have a direct facilitating effect on tumor growth and on the marrow microenvironment. Further studies of the biology of behind this observation are warranted. Characteristic N Median (range) Gender male 61 CRP 81 0.4mg/L (0.01–11.2) Albumin 99 3.6 g/dL (2.6–5.4) B2microglobulin 94 4.0 (0.9–28) μg/mL Marrow PC% 90 45% (11–99) PC labeling index 90 high (&gt;1%) 36 BM CD8 cells 100 270 (33 – &gt;300) ISS 94 1 19 2 41 3 34 Figure Figure

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