scholarly journals Selective Expansion of Cross-Reactive Cd8+ Memory T Cells by Viral Variants

1999 ◽  
Vol 190 (9) ◽  
pp. 1319-1328 ◽  
Author(s):  
John B.A.G. Haanen ◽  
Monika C. Wolkers ◽  
Ada M. Kruisbeek ◽  
Ton N.M. Schumacher
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza A ◽  
Memory T Cells ◽  
Cytotoxic T Cells ◽  
Population Based ◽  
T Cell Response ◽  
Natural Variants

The role of memory T cells during the immune response against random antigenic variants has not been resolved. Here, we show by simultaneous staining with two tetrameric major histocompatibility complex (MHC)–peptide molecules, that the polyclonal CD8+ T cell response against a series of natural variants of the influenza A nucleoprotein epitope is completely dominated by infrequent cross-reactive T cells that expand from an original memory population. Based on both biochemical and functional criteria, these cross-reactive cytotoxic T cells productively recognize both the parental and the mutant epitope in vitro and in vivo. These results provide direct evidence that the repertoire of antigen-specific T cells used during an infection critically depends on prior antigen encounters, and indicate that polyclonal memory T cell populations can provide protection against a range of antigenic variants.

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 Development of Stable Chimeric IL-15 for Trans-Presentation by the Antigen Presenting Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Manoj Patidar ◽  
Naveen Yadav ◽  
Sarat K. Dalai
Keyword(s):  
T Cells ◽  
T Cell ◽  
Half Life ◽  
Therapeutic Potential ◽  
Chimeric Protein ◽  
Antigen Presenting Cells ◽  
T Cell Response ◽  
Antigen Presenting

IL-15 is one of the important biologics considered for vaccine adjuvant and treatment of cancer. However, a short half-life and poor bioavailability limit its therapeutic potential. Herein, we have structured IL-15 into a chimeric protein to improve its half-life enabling greater bioavailability for longer periods. We have covalently linked IL-15 with IgG2 base to make the IL-15 a stable chimeric protein, which also increased its serum half-life by 40 fold. The dimeric structure of this kind of IgG based biologics has greater stability, resistance to proteolytic cleavage, and less frequent dosing schedule with minimum dosage for achieving the desired response compared to that of their monomeric forms. The structured chimeric IL-15 naturally forms a dimer, and retains its affinity for binding to its receptor, IL-15Rβ. Moreover, with the focused action of the structured chimeric IL-15, antigen-presenting cells (APC) would transpresent chimeric IL-15 along with antigen to the T cell, that will help the generation of quantitatively and qualitatively better antigen-specific memory T cells. In vitro and in vivo studies demonstrate the biological activity of chimeric IL-15 with respect to its ability to induce IL-15 signaling and modulating CD8+ T cell response in favor of memory generation. Thus, a longer half-life, dimeric nature, and anticipated focused transpresentation by APCs to the T cells will make chimeric IL-15 a super-agonist for memory CD8+ T cell responses.

scholarly journals The PPARα pathway in Vγ9Vδ2 T cell anergy

2014 ◽  
Vol 19 (4) ◽  
Author(s):  
Mary Poupot ◽  
Frédéric Boissard ◽  
Delphine Betous ◽  
Laure Bardouillet ◽  
Séverine Fruchon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
T Cell Response ◽  
T Cell Anergy ◽  
Pathway Activation ◽  
In Vitro Response ◽  
Vγ9vδ2 T Cells

AbstractPhosphoantigens (PAgs) activate Vγ9Vδ2 T lymphocytes, inducing their potent and rapid response in vitro and in vivo. However, humans and nonhuman primates that receive repeated injections of PAgs progressively lose their Vγ9Vδ2 T cell response to them. To elucidate the molecular mechanisms of this in vivo desensitization, we analyzed the transcriptome of circulating Vγ9Vδ2 T cells from macaques injected with PAg. We showed that three PAg injections induced the activation of the PPARα pathway in Vγ9Vδ2 T cells. Thus, we analyzed the in vitro response of Vγ9Vδ2 T cells stimulated with a PPARα agonist. We demonstrated that in vitro PPARα pathway activation led to the inhibition of the BrHPP-induced activation and proliferation of human Vγ9Vδ2 T cells. Since the PPARα pathway is involved in the antigen-selective desensitization of human Vγ9Vδ2 T cells, the use of PPARα inhibitors could enhance cancer immunotherapy based on Vγ9Vδ2 T cells.

scholarly journals The influenza A virus nucleoprotein gene controls the induction of both subtype specific and cross-reactive cytotoxic T cells.

1984 ◽  
Vol 160 (2) ◽  
pp. 552-563 ◽  
Author(s):  
A R Townsend ◽  
J J Skehel
Keyword(s):  
T Cells ◽  
Influenza A ◽  
Cytotoxic T Cells ◽  
Target Cells ◽  
Spleen Cells ◽  
Influenza A Viruses ◽  
Group A ◽  
Selection Of

Using genetically typed recombinant influenza A viruses that differ only in their genes for nucleoprotein, we have demonstrated that repeated stimulation in vitro of C57BL/6 spleen cells primed in vivo with E61-13-H17 (H3N2) virus results in the selection of a population of cytotoxic T lymphocytes (CTL) whose recognition of infected target cells maps to the gene for nucleoprotein of the 1968 virus. Influenza A viruses isolated between 1934 and 1979 fall into two groups defined by their ability to sensitize target cells for lysis by these CTL: 1934-1943 form one group (A/PR/8/34 related) and 1946-1979 form the second group (A/HK/8/68 related). These findings complement and extend our previous results with an isolated CTL clone with specificity for the 1934 nucleoprotein (27, 28). It is also shown that the same spleen cells derived from mice primed with E61-13-H17 virus in vivo, but maintained in identical conditions by stimulation with X31 virus (which differs from the former only in the origin of its gene for NP) in vitro, results in the selection of CTL that cross-react on target cells infected with A/PR/8/1934 (H1N1) or A/Aichi/1968 (H3N2). These results show that the influenza A virus gene for NP can play a role in selecting CTL with different specificities and implicate the NP molecule as a candidate for a target structure recognized by both subtype-directed and cross-reactive influenza A-specific cytotoxic T cells.

132. IMMUNE-DEVIATING CYTOKINES DETERMINE THE MATERNAL T CELL RESPONSE DURING PREGNANCY AND TOLERANCE OR REJECTION OF THE CONCEPTUS

2009 ◽  
Vol 21 (9) ◽  
pp. 51
Author(s):  
L. M. Moldenhauer ◽  
J. D. Hayball ◽  
S. A. Robertson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Tolerance ◽  
Cell Response ◽  
Fetal Loss ◽  
T Cell Response ◽  
Cell Phenotype ◽  
Fetal Survival

In healthy pregnancies the maternal immune system establishes paternal antigen-specific tolerance allowing survival of the semi-allogeneic conceptus. The cytokine environment is a key factor in determining the phenotype of antigen-specific lymphocytes, influencing the development of either cytotoxic or tolerogenic cells. We hypothesized that the cytokine environment at the time of priming to paternal antigens influences the phenotype of the maternal T cell response and pregnancy outcome. Transgenic Act-mOVA male mice expressing chicken ovalbumin (OVA) ubiquitously provided OVA as a model paternal antigen. OVA is present within the semen of Act-mOVA mice and is inherited and expressed by the conceptus tissue. OVA-reactive CD8+ OT-I T cells were activated with OVA in the presence of various immune-deviating cytokines in vitro, before transfer at 3.5 dpc to C57Bl/6 (B6) females gestating OVA-expressing fetuses. Pregnant mice received either naïve OT-I T cells, cytotoxic OT-I T cells stimulated in vitro in the presence of IL-2 or OT-I T cells stimulated in vitro in the presence of TGFβ1 and IL-10, two factors present in the uterus and associated with immune tolerance. Immunohistochemistry was utilized to demonstrate that OT-I T cells infiltrate into the implantation site. Cytotoxic OT-I T cells caused fetal loss, while OT-I T cells activated in vivo or in vitro with TGFβ1 and IL-10 did not cause fetal loss. Additionally, cytotoxic OT-I T cells did not affect B6 x B6 matings, demonstrating the antigen-specific nature of the T cell-mediated fetal loss. Collectively these experiments show that maternal antigen-reactive T cells activated in vivo in the cytokine environment of the mated uterus are tolerogenic, not cytotoxic, and implicate TGFβ1 and IL-10 as key elements of that environment. We conclude that the cytokine environment at the time of priming to paternal antigens influences the T cell phenotype and impacts upon maternal immune tolerance and fetal survival.

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.

Activation of T and NK Cells Following Lenalidomide Therapy in Patients with Follicular Lymphoma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2766-2766
Author(s):  
Seema Rawal ◽  
Nathan Fowler ◽  
Min Zhang ◽  
Zhiqiang Wang ◽  
Tariq Muzzafar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Nk Cells ◽  
Research Funding ◽  
Memory T Cells ◽  
T Cell Subsets ◽  
Central Memory T Cells

Abstract Abstract 2766 Background: Lenalidomide plus rituximab therapy is a highly effective and well-tolerated therapy in patients (pts) with follicular lymphoma (FL). In a Phase II trial, this combination induced a complete remission rate of 87% in pts with advanced stage untreated FL (Fowler et al, Ann Oncol, 2011; 22; suppl 4:137). A randomized Phase III trial was recently initiated to compare this combination with current standard of care therapies in pts with FL. Although lenalidomide is known to be an immunomodulatory drug with effects on a variety of immune cells in vitro, its effects have not been well studied in vivo in humans. Understanding the in vivo effects of lenalidomide could lead to novel combination strategies to enhance the efficacy and improve clinical outcome in FL and other malignancies. Methods: Pts received lenalidomide 20 mg/day on days 1–21 of each 28-day cycle and rituximab was given at 375 mg/m2on day 1 of each cycle. Peripheral blood mononuclear cells (PBMC) were phenotyped by multiparametric flow cytometry at baseline, on cycle 2 day 15 (C2D15), and at the end of cycle 6. In addition, peripheral blood (PB) samples were collected in PAXgene Blood RNA tubes at baseline and on C2D15 for whole genome gene expression profiling (GEP). Results: Immunophenotyping of baseline and end of cycle 6 PBMC (n=17) showed that the percentages and absolute numbers of CD3+, CD4+, CD8+, TCRgd, and Foxp3+ regulatory T cells; and NK, NKT, and myeloid dendritic cells were not significantly different between the two time points. However, a significant increase in CD4+CD45RO+ (p<0.01) and CD8+CD45RO+ (p=0.04) memory T cells was observed post-therapy. Further characterization of CD4+ T cells showed a significant increase in central memory T cells (p<0.001) and a decrease in naïve (p<0.01) and terminally differentiated (p<0.01) T cells, but no change in effector memory T cells. The increase in CD8+ central memory T cells was marginally significant (p=0.06). Plasmacytoid dendritic cells (PDC) were also significantly increased (p=0.02). In contrast, no such changes in T cell subsets or PDC were observed in FL pts (n=9) treated with 6 cycles of R-CHOP chemotherapy that received equal number of rituximab doses and analyzed at similar time points (baseline and end of cycle 6). To understand lenalidomide-induced changes on a molecular level, we compared GEP data at C2D15 vs. baseline for 7 pairs of PB samples. The paired significance analysis of microarrays method, based on Student's t test, identified 1,748 differentially expressed genes (DEG; 713 up, 1035 down), without a fold-change threshold, in C2D15 samples vs. baseline. Results were influenced by rituximab-induced depletion of B cells in C2D15 samples, but there were many changes that suggested altered PBMC physiology. Noteworthy up-regulated genes (>1.5 fold) included genes associated with T and NK cell activation including BATF, CCR2, CD1B, CD2, CD160, CTLA4, CXCR3, ICOS, and LAG3; and CD163 and CD209, phagocytic receptors expressed on monocytes/macrophages. Down-regulated genes (>1.5 fold) included CXCR5, which mediates B cell migration into follicles; and IL1B and TNFSF13B (BAFF), which are produced by activated macrophages and induce B cell proliferation. Gene set enrichment analysis of all GEP results, and Ingenuity Pathway Analysis of DEGs, indicated up regulation of multiple pathways and processes including ribosomal and mitochondrial components involved in translation and oxidative phosphorylation, CTLA4 signaling in cytotoxic T cells, and differentiation and signaling by ICOS and CD28 in T helper cells. We confirmed up regulation of CTLA4, ICOS, and LAG3 at the protein level in C2D15 PBMC by flow cytometry. Furthermore, treatment of PBMC derived from untreated FL pts with lenalidomide in vitro resulted in up regulation of these molecules in T and/or NK cells consistent with our in vivo results. Conclusions: In FL pts, lenalidomide induced multiple changes in the immune system including increases in PDC and memory T cell subsets, activation of T and NK cells, and down-regulation of certain genes mediating B cell migration and proliferation. These results provide insights into the mechanism of action of lenalidomide and suggest that it can be combined with other immunostimulatory agents such as therapeutic vaccines, adoptive T cell therapy strategies, and immune checkpoint inhibitors to further enhance its efficacy in FL and other malignancies. Disclosures: Fowler: Celgene: Research Funding. Heise:Celgene Corporation: Employment, Equity Ownership. Lacerte:Celgene: Honoraria. Samaniego:Celgene: Research Funding. Neelapu:Celgene Corporation: Research Funding.

scholarly journals Functional Avidity: A Measure to Predict the Efficacy of Effector T Cells?

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Selena Viganò ◽  
Daniel T. Utzschneider ◽  
Matthieu Perreau ◽  
Giuseppe Pantaleo ◽  
Dietmar Zehn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Cell Populations ◽  
High Avidity ◽  
Chronic Infections ◽  
Functional Avidity ◽  
Cognate Antigen

The functional avidity is determined by exposing T-cell populationsin vitroto different amounts of cognate antigen. T-cells with high functional avidity respond to low antigen doses. Thisin vitromeasure is thought to correlate well with thein vivoeffector capacity of T-cells. We here present the multifaceted factors determining and influencing the functional avidity of T-cells. We outline how changes in the functional avidity can occur over the course of an infection. This process, known as avidity maturation, can occur despite the fact that T-cells express a fixed TCR. Furthermore, examples are provided illustrating the importance of generating T-cell populations that exhibit a high functional avidity when responding to an infection or tumors. Furthermore, we discuss whether criteria based on which we evaluate an effective T-cell response to acute infections can also be applied to chronic infections such as HIV. Finally, we also focus on observations that high-avidity T-cells show higher signs of exhaustion and facilitate the emergence of virus escape variants. The review summarizes our current understanding of how this may occur as well as how T-cells of different functional avidity contribute to antiviral and anti-tumor immunity. Enhancing our knowledge in this field is relevant for tumor immunotherapy and vaccines design.

scholarly journals The interaction between CD8+ cytotoxic T cells and Leishmania-infected macrophages.

1991 ◽  
Vol 174 (3) ◽  
pp. 499-505 ◽  
Author(s):  
L E Smith ◽  
M Rodrigues ◽  
D G Russell
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Clone ◽  
Cytotoxic T Cells ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
T Cell Clone ◽  
Vitro Model ◽  
Leishmania Parasites

Leishmania is resident within the macrophages of its vertebrate host. In any intramacrophage infection, where the pathogen is present in a form capable of mediating cell to cell transmission, the contribution of a cytotoxic T cell response to protective immunity is questionable. This study presents data from an in vitro model designed to elucidate the outcome of an interaction between CD8+, cytotoxic T cells and infected macrophages. Experiments were conducted with an H-2d-restricted, cytotoxic CD8+ T cell clone and Leishmania parasites present in mixed macrophage cultures, with the parasites confined to either histocompatible BALB/c macrophages, or incompatible CBA macrophages. Initial experiments indicated that the viability of Leishmania was unaffected by the lysis of its host macrophage by cytotoxic T cells. However, extended experiments showed that the parasites were killed between 24 and 72 h. The same results were obtained regardless of whether the parasites were resident in the target, BALB/c, macrophages or the bystander, CBA, macrophages. Addition of neutralizing, anti-IFN-g antibody to the cultures ablated most of the leishmanicidal behavior, indicating that parasite death was attributable to macrophage activation, resulting from cytokine secretion from the T cells following the initial recognition event.

scholarly journals An exogenous mouse mammary tumor virus with properties of Mls-1a (Mtv-7).

1992 ◽  
Vol 175 (6) ◽  
pp. 1623-1633 ◽  
Author(s):  
W Held ◽  
A N Shakhov ◽  
G Waanders ◽  
L Scarpellino ◽  
R Luethy ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mammary Tumor ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Clonal Deletion ◽  
Isolation And Characterization ◽  
Mouse Mammary Tumor

The classical minor lymphocyte stimulating (Mls) antigens, which induce a strong primary T cell response in vitro, are closely linked to endogenous copies of mouse mammary tumor viruses (MMTV). Expression of Mls genes leads to clonal deletion of T cell subsets expressing specific T cell receptor (TCR) V beta chains. We describe the isolation and characterization of a new exogenous (infectious) MMTV with biological properties similar to the Mls antigen Mls-1a. In vivo administration of either Mls-1a-expressing B cells or the infectious MMTV (SW) led to an increase of T cells expressing V beta 6 followed by their deletion. Surprisingly, different kinetics of deletion were observed with the exogenous virus depending upon the route of infection. Infection through the mucosa led to a slow deletion of V beta 6+ T cells, whereas deletion was rapid after subcutaneous infection. Sequence analysis of the open reading frames in the 3' long terminal repeat of both this exogenous MMTV (SW) and of Mtv-7 (which is closely linked to Mls-1a) revealed striking similarities, particularly in the COOH terminus, which has been implicated in TCR V beta recognition. The identification of an infectious MMTV with the properties of a strong Mls antigen provides a new, powerful tool to study immunity and tolerance in vivo.

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