979. Antigen-Transduced T Cell Blasts Specifically Delete Antigen-Specific Cytotoxic T Cells and Induce a CD4+-CD25+- Regulatory T Cell Response

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.

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

Blood ◽

10.1182/blood.v104.11.1354.1354 ◽

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.

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Hepatitis C Virus Induces Regulatory T Cells by Naturally Occurring Viral Variants to Suppress T Cell Responses

Clinical and Developmental Immunology ◽

10.1155/2011/806061 ◽

2011 ◽

Vol 2011 ◽

pp. 1-15 ◽

Cited By ~ 17

Author(s):

Matthew F. Cusick ◽

Jennifer J. Schiller ◽

Joan C. Gill ◽

David D. Eckels

Keyword(s):

T Cells ◽

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Regulatory T Cell ◽

Cell Response ◽

T Cell Response ◽

Cell Responses ◽

Naturally Occurring ◽

Specific Manner

Regulatory T cell markers are increased in chronically infected individuals with the hepatitis C virus (HCV), but to date, the induction and maintenance of Tregs in HCV infection has not been clearly defined. In this paper, we demonstrate that naturally occurring viral variants suppress T cell responses to cognate NS3358-375in an antigen-specific manner. Of four archetypal variants, S370P induced regulatory T cell markers in comparison to NS3358-375-stimulated CD4 T cells. Further, the addition of variant-specific CD4 T cells back into a polyclonal culture in a dose-dependent manner inhibited the T cell response. These results suggest that HCV is able to induce antigen-specific regulatory T cells to suppress the antiviral T cell response in an antigen-specific manner, thus contributing to a niche within the host that could be conducive to HCV persistence.

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Mycobacterium bovis BCG Vaccination Induces Divergent Proinflammatory or Regulatory T Cell Responses in Adults

Clinical and Vaccine Immunology ◽

10.1128/cvi.00162-15 ◽

2015 ◽

Vol 22 (7) ◽

pp. 778-788 ◽

Cited By ~ 31

Author(s):

Mardi C. Boer ◽

Corine Prins ◽

Krista E. van Meijgaarden ◽

Jaap T. van Dissel ◽

Tom H. M. Ottenhoff ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mycobacterium Bovis ◽

Regulatory T Cell ◽

Cell Response ◽

T Cell Response ◽

Bcg Vaccination ◽

Cell Responses ◽

Tnf Α ◽

Ifn Γ

ABSTRACTMycobacterium bovisbacillus Calmette-Guérin (BCG), the only currently available vaccine against tuberculosis, induces variable protection in adults. Immune correlates of protection are lacking, and analyses on cytokine-producing T cell subsets in protected versus unprotected cohorts have yielded inconsistent results. We studied the primary T cell response, both proinflammatory and regulatory T cell responses, induced by BCG vaccination in adults. Twelve healthy adult volunteers who were tuberculin skin test (TST) negative, QuantiFERON test (QFT) negative, and BCG naive were vaccinated with BCG and followed up prospectively. BCG vaccination induced an unexpectedly dichotomous immune response in this small, BCG-naive, young-adult cohort: BCG vaccination induced either gamma interferon-positive (IFN-γ+) interleukin 2-positive (IL-2+) tumor necrosis factor α-positive (TNF-α+) polyfunctional CD4+T cells concurrent with CD4+IL-17A+and CD8+IFN-γ+T cells or, in contrast, virtually absent cytokine responses with induction of CD8+regulatory T cells. Significant induction of polyfunctional CD4+IFN-γ+IL-2+TNF-α+T cells and IFN-γ production by peripheral blood mononuclear cells (PBMCs) was confined to individuals with strong immunization-induced local skin inflammation and increased serum C-reactive protein (CRP). Conversely, in individuals with mild inflammation, regulatory-like CD8+T cells were uniquely induced. Thus, BCG vaccination either induced a broad proinflammatory T cell response with local inflammatory reactogenicity or, in contrast, a predominant CD8+regulatory T cell response with mild local inflammation, poor cytokine induction, and absent polyfunctional CD4+T cells. Further detailed fine mapping of the heterogeneous host response to BCG vaccination using classical and nonclassical immune markers will enhance our understanding of the mechanisms and determinants that underlie the induction of apparently opposite immune responses and how these impact the ability of BCG to induce protective immunity to TB.

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Potentiating the Antitumor Activity of Cytotoxic T Cells via the Transmembrane Domain of IGSF4 That Increases TCR Avidity

Frontiers in Immunology ◽

10.3389/fimmu.2020.591054 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hye-Ran Kim ◽

Jeong-Su Park ◽

Yasmin Fatima ◽

Maiza Kausar ◽

Jin-Hwa Park ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antitumor Activity ◽

Cell Response ◽

Transmembrane Domain ◽

Cytotoxic T Cells ◽

T Cell Response ◽

Immunoglobulin Superfamily ◽

B16f10 Tumor ◽

Tm Domain

A robust T-cell response is an important component of sustained antitumor immunity. In this respect, the avidity of TCR in the antigen-targeting of tumors is crucial for the quality of the T-cell response. This study reports that the transmembrane (TM) domain of immunoglobulin superfamily member 4 (IGSF4) binds to the TM of the CD3 ζ-chain through an interaction between His177 and Asp36, which results in IGSF4-CD3 ζ dimers. IGSF4 also forms homo-dimers through the GxxVA motif in the TM domain, thereby constituting large TCR clusters. Overexpression of IGSF4 lacking the extracellular (IG4ΔEXT) domain potentiates the OTI CD8+ T cells to release IFN-γ and TNF-α and to kill OVA+-B16F10 melanoma cells. In animal models, IG4ΔEXT significantly reduces B16F10 tumor metastasis as well as tumor growth. Collectively, the results indicate that the TM domain of IGSF4 can regulate TCR avidity, and they further demonstrate that TCR avidity regulation is critical for improving the antitumor activity of cytotoxic T cells.

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.763379 ◽

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.

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Interferon-α, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia

Blood ◽

10.1182/blood-2002-02-0659 ◽

2003 ◽

Vol 101 (1) ◽

pp. 259-264 ◽

Cited By ~ 102

Author(s):

Andreas Burchert ◽

Stefan Wölfl ◽

Manuel Schmidt ◽

Cornelia Brendel ◽

Barbara Denecke ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Chronic Myeloid Leukemia ◽

Peripheral Blood ◽

Cell Response ◽

Myeloid Leukemia ◽

Cytotoxic T Cells ◽

T Cell Response ◽

Interferon Α ◽

Hematopoietic Stem

Abstract Chronic myeloid leukemia (CML) is a clonal disease of hematopoietic stem cells caused by a reciprocal translocation of the long arms of chromosomes 9 and 22. In human leukocyte antigen A*0201+ (HLA-A*0201+) individuals, response after interferon-α (IFN-α) was shown to be associated with the emergence of CML-specific cytotoxic T cells that recognize PR-1, a myeloblastin (MBN)–derived nonapeptide. In contrast, imatinib potently induces remissions from CML by specific inhibition of the ABL tyrosine kinase. Here, we explored molecular regulations associated with CML responses under different treatment forms using cDNA-array. Expression of MBN was found to be down-regulated in remission under imatinib therapy (0 of 7MBN+ patients). In contrast, MBNtranscription was readily detectable in the peripheral blood in 8 of 8 tested IFN-α patients in complete remission (P = .0002). IFN-α–dependent MBNtranscription was confirmed in vitro by stimulation of peripheral blood mononuclear cells (PBMCs) with IFN-α and by IFN-α–mediated activation of the MBN promoter in reporter gene assays. Finally, with the use of HLA-A*0201–restricted,MBN-specific tetrameric complexes, it was demonstrated that all of 4 IFN-α–treated patients (100%), but only 2 of 11 imatinib patients (19%), in complete hematological or cytogenetic remission developed MBN-specific cytotoxic T cells (P = .011). Together, the induction of MBNexpression by IFN-α, but not imatinib, may contribute to the specific ability of IFN-α to induce an MBN-specific T-cell response in CML patients. This also implies that the character of remissions achieved with either drug may not be equivalent and therefore a therapy modality combining IFN-α and imatinib may be most effective.

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Distinct Kinetics of Effector CD8+ Cytotoxic T Cells after Infection with Trypanosoma cruzi in Naïve or Vaccinated Mice

Infection and Immunity ◽

10.1128/iai.74.4.2477-2481.2006 ◽

2006 ◽

Vol 74 (4) ◽

pp. 2477-2481 ◽

Cited By ~ 72

Author(s):

Fanny Tzelepis ◽

Bruna C. G. de Alencar ◽

Marcus L. O. Penido ◽

Ricardo T. Gazzinelli ◽

Pedro M. Persechini ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Trypanosoma Cruzi ◽

Cell Response ◽

Cytotoxic T Cells ◽

T Cell Responses ◽

T Cell Response ◽

Cell Responses ◽

Microbial Infections ◽

Kinetics Of

ABSTRACT The kinetics of effector CD8+-T-cell responses to specific Trypanosoma cruzi epitopes was investigated after challenge. Our results suggest that the delayed kinetics differs from that observed in other microbial infections and facilitates the establishment of the disease in naïve mice. In contrast, in vaccinated mice, the swift CD8+-T-cell response helps host survival after challenge.

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