scholarly journals 612 Human CLEC9A antibodies deliver NY-ESO-1 antigen to CD141+ dendritic cells to activate naïve and memory NY-ESO-1-specific CD8+ T cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A648-A648
Author(s):  
Kelly-Anne Masterman ◽  
Oscar Haigh ◽  
Kirsteen Tullett ◽  
Ingrid Leal-Rojas ◽  
Carina Walpole ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Ethics Committee ◽  
Cross Presentation ◽  
Cell Responses ◽  
Melanoma Patients

BackgroundDendritic cells (DC) are crucial for the efficacy of cancer vaccines, but current vaccines do not harness the key cDC1 subtype required for effective CD8+ T cell mediated tumor immune responses. Vaccine immunogenicity could be enhanced by specific delivery of immunogenic tumor antigens to CD141+ DC, the human cDC1 equivalent. CD141+ DC exclusively express the C-type-lectin-like receptor CLEC9A, which is important for the regulation of CD8+ T cell responses. This study developed a new vaccine that harnesses a human anti-CLEC9A antibody to specifically deliver the immunogenic tumor antigen, NY-ESO-1 to human CD141+ DC. The ability of the CLEC9A-NY-ESO-1 antibody to activate NY-ESO-1 specific naïve and memory CD8+ T cells was examined and compared to a vaccine comprised of a human DEC-205-NY-ESO-1 antibody that targets all human DC.MethodsHuman anti-CLEC9A, anti-DEC-205 and isotype control IgG4 antibodies were genetically fused to NY-ESO-1 polypeptide. Cross-presentation to NY-ESO-1- epitope specific CD8+ T cells and reactivity of T cell responses in melanoma patients was assessed by IFNγ production following incubation of CD141+ DC and patient peripheral blood mononuclear cells with targeting antibodies. Humanized mice containing human DC subsets and a repertoire of naïve NY-ESO-1-specific CD8+ T cells were used to investigate naïve T cell priming. T cell effector function was measured by expression of IFNγ, MIP-1β, TNF and CD107a and by lysis of target tumor cells.ResultsCLEC9A-NY-ESO-1 Ab were effective at mediating delivery and cross-presentation of multiple NY-ESO-1 epitopes by CD141+ DC for activation of NY-ESO-1-specific CD8+ T cells. When benchmarked to NY-ESO-1 conjugated to an untargeted control antibody or to anti-human DEC-205, CLEC9A-NY-ESO-1 was superior at ex vivo reactivation of NY-ESO-1-specific T cell responses in melanoma patients. Moreover, CLEC9A-NY-ESO-1 induced priming of naïve NY-ESO-1-specific CD8+ T cells with polyclonal effector function and potent tumor killing capacity in vitro.ConclusionsThese data advocate human CLEC9A-NY-ESO-1 antibody as an attractive strategy for specific targeting of CD141+ DC to enhance tumour immunogenicity in NY-ESO-1-expressing malignancies.Ethics ApprovalWritten informed consent was obtained for human sample acquisition in line with standards established by the Declaration of Helsinki. Study approval was granted by the Mater Human Research Ethics Committee (HREC13/MHS/83 and HREC13/MHS/86) and The U.S. Army Medical Research and Materiel Command (USAMRMC) Office of Research Protections, Human Research Protection Office (HRPO; A-18738.1, A-18738.2, A-18738.3). All animal experiments were approved by the University of Queensland Animal Ethics Committee and conducted in accordance with the Australian Code for the Care and Use of Animals for Scientific Purposes in addition to the laws of the United States and regulations of the Department of Agriculture.

scholarly journals Cross-priming CD8+ T cells by targeting antigens to human dendritic cells through DCIR

Blood ◽  
2010 ◽  
Vol 116 (10) ◽  
pp. 1685-1697 ◽  
Author(s):  
Eynav Klechevsky ◽  
Anne-Laure Flamar ◽  
Yanying Cao ◽  
Jean-Philippe Blanck ◽  
Maochang Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Immunity ◽  
Cross Presentation ◽  
Cell Responses ◽  
Cell Immunity

Abstract We evaluated human CD8+ T-cell responses generated by targeting antigens to dendritic cells (DCs) through various lectin receptors. We found the immunoreceptor tyrosine-based inhibitory motif-containing DC immunoreceptor (DCIR) to mediate potent cross-presentation. A single exposure to a low dose of anti-DCIR–antigen conjugate initiated antigen-specific CD8+ T-cell immunity by all human DC subsets including ex vivo–generated DCs, skin-isolated Langerhans cells, and blood myeloid DCs and plasmacytoid DCs. The delivery of influenza matrix protein (FluMP) through DCIR resulted in expansion of FluMP-specific memory CD8+ T cells. Enhanced specific CD8+ T-cell responses were observed when an antigen was delivered to the DCs via DCIR, compared with those induced by a free antigen, or antigen conjugated to a control monoclonal antibody or delivered via DC-SIGN, another lectin receptor. DCIR targeting also induced primary CD8+ T-cell responses against self (MART-1) and viral (HIV gag) antigens. Addition of Toll-like receptor (TLR) 7/8 agonist enhanced DCIR-mediated cross-presentation as well as cross-priming, particularly when combined with a CD40 signal. TLR7/8 activation was associated with increased expansion of the primed CD8+ T cells, high production of interferon-γ and tumor necrosis factor-α, and reduced levels of type 2–associated cytokines. Thus, antigen targeting via the human DCIR receptor allows activation of specific CD8+ T-cell immunity.

scholarly journals Mesothelin-specific CD8+ T Cell Responses Provide Evidence of In Vivo Cross-Priming by Antigen-Presenting Cells in Vaccinated Pancreatic Cancer Patients

2004 ◽  
Vol 200 (3) ◽  
pp. 297-306 ◽  
Author(s):  
Amy Morck Thomas ◽  
Lynn M. Santarsiero ◽  
Eric R. Lutz ◽  
Todd D. Armstrong ◽  
Yi-Cheng Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cross Presentation ◽  
Cell Responses ◽  
Antigen Presenting

Tumor-specific CD8+ T cells can potentially be activated by two distinct mechanisms of major histocompatibility complex class I–restricted antigen presentation as follows: direct presentation by tumor cells themselves or indirect presentation by professional antigen-presenting cells (APCs). However, controversy still exists as to whether indirect presentation (the cross-priming mechanism) can contribute to effective in vivo priming of tumor-specific CD8+ T cells that are capable of eradicating cancer in patients. A clinical trial of vaccination with granulocyte macrophage–colony stimulating factor–transduced pancreatic cancer lines was designed to test whether cross-presentation by locally recruited APCs can activate pancreatic tumor-specific CD8+ T cells. Previously, we reported postvaccination delayed-type hypersensitivity (DTH) responses to autologous tumor in 3 out of 14 treated patients. Mesothelin is an antigen demonstrated previously by gene expression profiling to be up-regulated in most pancreatic cancers. We report here the consistent induction of CD8+ T cell responses to multiple HLA-A2, A3, and A24-restricted mesothelin epitopes exclusively in the three patients with vaccine-induced DTH responses. Importantly, neither of the vaccinating pancreatic cancer cell lines expressed HLA-A2, A3, or A24. These results provide the first direct evidence that CD8 T cell responses can be generated via cross-presentation by an immunotherapy approach designed to recruit APCs to the vaccination site.

scholarly journals Mechanisms of induction of CD8⁺ T cell responses by dendritic cells

2021 ◽  
Author(s):  
◽  
Taryn Louise Osmond
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cross Presentation ◽  
Cell Responses ◽  
Circulating Antigen

<p>Splenic CD8α⁺ dendritic cells (DCs) have been described as key antigen presenting cells for the induction of CD8⁺ T cell responses to circulating antigen. This is through a heightened capacity to acquire and present the antigens via the process of cross-presentation, expression of high levels of the co-stimulatory and adhesion molecules required to stimulate CD8⁺ T cells, and the capacity to release high levels of the cytokines required to drive differentiation of CD8⁺ T cells into cytotoxic T lymphocytes (CTLs). However, recent research has indicated that the splenic CD8α⁺ DC population is more heterogeneous than originally thought. A previous study from my own laboratory suggested that a population of CD8α⁺ DCs that express the c-type lectin langerin primarily possess the heightened functions previously attributed to the total CD8α⁺ population. Therefore, the aim of this thesis research was to explore this subset of DCs in more detail, with specific emphasis on gaining mechanistic insight into their ability to elicit CD8⁺ T cell responses to circulating proteins. In the first section of this thesis, the hypothesis that the splenic langerin⁺ CD8α⁺ DCs were the critical subset involved in the induction of strong systemic CD8⁺ T cell responses to circulating antigen was tested in detail. This was examined using a genetically modified mouse model in which langerin-expressing cells could be easily identified and/or specifically depleted. It was first shown that the induction of CD8⁺ T cell responses to the model antigen ovalbumin was dependent on entry into the spleen in the presence of appropriate stimulation, which in these studies was provided by agonists for the toll-like receptors (TLRs) and/or signals from innate-like lymphocytes called natural killer T (NKT) cells. The primary targets for these signals were shown to be splenic langerin⁺ CD8α⁺ DCs, as CD8⁺ T cell responses were significantly reduced in hosts depleted of these cells within the spleen. Furthermore, agonists for TLRs that were not expressed by langerin⁺ CD8α⁺ DCs failed to enhance T cell responses. The langerin⁺ CD8α⁺ DCs were shown to be located in the marginal zone of the spleen, where they could readily screen the blood for antigens, and their function was critical to the induction of CD8⁺ T cell responses within six hours of antigen delivery. Interestingly, other local langerin-negative antigen presenting cells (APCs) were shown to be capable of cross-presentation, but with significantly reduced capacity to prime CD8⁺ T cell responses. Therefore, in the second section of this thesis the hypothesis that the langerin-negative APCs were capable of contributing to CD8⁺ T cell responses with appropriately timed stimuli was investigated. One of the downstream effects of inducing NKT cell activation at the time of priming was shown to be the “pre-conditioning” of langerin-negative DCs, allowing them to respond strongly to subsequent TLR ligation. Using SiglecH-DTR mice, it was shown that plasmacytoid DCs (which are langerin-negative) were pre-conditioned by NKT cell activation, allowing them to respond more actively to the delayed TLR stimulation by producing significantly enhanced levels of IFN-α. This factor was also potentially responsible for “feeding back” to the CD8α⁺ DCs (including langerin-expressing CD8α⁺ DCs), to enhance their function, as indicated by increases in cytokine production. Significantly, the major langerin-negative DC populations, defined as CD8α⁻ DCs, were pre-conditioned to have an enhanced cytokine release response to subsequent stimulation through TLR7, a receptor not expressed by langerin-positive DCs. This enhanced ability to respond to TLR7 ligation permitted these langerin-negative APCs to contribute to increased CD8⁺ T cell accumulation, with enhanced functional activity. Importantly, the CD8⁺ T cell response induced remained significantly dependent on initial cross-priming by langerin⁺ CD8α⁺ DCs, and it was only through pre-conditioning that langerinnegative APCs could contribute to enhancing the T cell response. In the third section of this thesis, the hypothesis that the CD8⁺ T cell responses generated in the presence of langerin⁺ CD8α⁺ DCs were phenotypically and functionally distinct from those responses generated in their absence was tested. No obvious differences were seen in CD8⁺ T cell homing, memory phenotype, restimulatory capacity, and expression of key molecules involved in metabolic function, survival and cytolytic function. However, in vivo cytotoxic function several weeks after priming was comparable, suggesting that this function was not related to initial burst size, providing some evidence of difference in function between CD8⁺ T cells primed in the presence or absence of langerin⁺ CD8α⁺ DCs. In summary, the splenic langerin⁺ CD8α⁺ DCs are the major subset responsible for cross-priming CD8⁺ T cell responses to circulating antigen, and for interpreting multiple stimulatory signals for enhancing the response. However, effective CD8⁺ T cell responses can be generated in their absence, particularly when antigens are provided in the context of appropriately temporally phased stimuli.</p>

scholarly journals Organized immune cell interactions within tumors sustain a productive T-cell response

2020 ◽  
Vol 33 (1) ◽  
pp. 27-37
Author(s):  
Maria A Cardenas ◽  
Nataliya Prokhnevska ◽  
Haydn T Kissick
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
T Cell Subsets ◽  
Cell Responses

Abstract Tumor-infiltrating CD8 T cells are associated with improved patient survival and response to immunotherapy in various cancers. Persistent antigen leads to CD8 T-cell exhaustion, where proliferation/self-renewal and killing are divided within distinct subsets of CD8 T cells in the tumor. CD8 T-cell responses in chronic antigen settings must be maintained for long periods of time, suggesting that mechanisms that regulate chronic CD8 T-cell responses may differ from those in acute settings. Currently, factors that regulate the maintenance of stem-like CD8 T cells in the tumor or their differentiation into terminally differentiated cells are unknown. In this review, we discuss the role of dendritic cells in the activation and differentiation of CD8 T-cell subsets within secondary lymphoid tissue and tumors. In addition, we examine changes in CD4 T-cell differentiation in response to chronic antigens and consider how subset-specific mechanisms could assist the stem-like and terminally differentiated CD8 T-cell subsets. Finally, we highlight how tumor-infiltrating CD4 T cells and dendritic cells interact with CD8 T cells within organized lymphoid-like areas in the tumor and propose a CD8 T-cell differentiation model that requires the collaboration of CD4 T cells and dendritic cells. These organized interactions coordinate the anti-tumor response and control disease progression by mechanisms that regulate CD8 T-cell differentiation, which permit the maintenance of an effective balance of stem-like and terminally differentiated CD8 T cells.

scholarly journals The Role of Nanovaccine in Cross-Presentation of Antigen-Presenting Cells for the Activation of CD8+ T Cell Responses

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 612 ◽  
Author(s):  
Cheol Gyun Kim ◽  
Yoon-Chul Kye ◽  
Cheol-Heui Yun
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Vaccine Development ◽  
Malignant Tumors ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cross Presentation ◽  
Cell Responses

Explosive growth in nanotechnology has merged with vaccine development in the battle against diseases caused by bacterial or viral infections and malignant tumors. Due to physicochemical characteristics including size, viscosity, density and electrostatic properties, nanomaterials have been applied to various vaccination strategies. Nanovaccines, as they are called, have been the subject of many studies, including review papers from a material science point of view, although a mode of action based on a biological and immunological understanding has yet to emerge. In this review, we discuss nanovaccines in terms of CD8+ T cell responses, which are essential for antiviral and anticancer therapies. We focus mainly on the role and mechanism, with particular attention to the functional aspects, of nanovaccines in inducing cross-presentation, an unconventional type of antigen-presentation that activates CD8+ T cells upon administration of exogenous antigens, in dendritic cells followed by activation of antigen-specific CD8+ T cell responses. Two major intracellular mechanisms that nanovaccines harness for cross-presentation are described; one is endosomal swelling and rupture, and the other is membrane fusion. Both processes eventually allow exogenous vaccine antigens to be exported from phagosomes to the cytosol followed by loading on major histocompatibility complex class I, triggering clonal expansion of CD8+ T cells. Advancement of nanotechnology with an enhanced understanding of how nanovaccines work will contribute to the design of more effective and safer nanovaccines.

scholarly journals Mechanisms of induction of CD8⁺ T cell responses by dendritic cells

2021 ◽  
Author(s):  
◽  
Taryn Louise Osmond
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cross Presentation ◽  
Cell Responses ◽  
Circulating Antigen

<p>Splenic CD8α⁺ dendritic cells (DCs) have been described as key antigen presenting cells for the induction of CD8⁺ T cell responses to circulating antigen. This is through a heightened capacity to acquire and present the antigens via the process of cross-presentation, expression of high levels of the co-stimulatory and adhesion molecules required to stimulate CD8⁺ T cells, and the capacity to release high levels of the cytokines required to drive differentiation of CD8⁺ T cells into cytotoxic T lymphocytes (CTLs). However, recent research has indicated that the splenic CD8α⁺ DC population is more heterogeneous than originally thought. A previous study from my own laboratory suggested that a population of CD8α⁺ DCs that express the c-type lectin langerin primarily possess the heightened functions previously attributed to the total CD8α⁺ population. Therefore, the aim of this thesis research was to explore this subset of DCs in more detail, with specific emphasis on gaining mechanistic insight into their ability to elicit CD8⁺ T cell responses to circulating proteins. In the first section of this thesis, the hypothesis that the splenic langerin⁺ CD8α⁺ DCs were the critical subset involved in the induction of strong systemic CD8⁺ T cell responses to circulating antigen was tested in detail. This was examined using a genetically modified mouse model in which langerin-expressing cells could be easily identified and/or specifically depleted. It was first shown that the induction of CD8⁺ T cell responses to the model antigen ovalbumin was dependent on entry into the spleen in the presence of appropriate stimulation, which in these studies was provided by agonists for the toll-like receptors (TLRs) and/or signals from innate-like lymphocytes called natural killer T (NKT) cells. The primary targets for these signals were shown to be splenic langerin⁺ CD8α⁺ DCs, as CD8⁺ T cell responses were significantly reduced in hosts depleted of these cells within the spleen. Furthermore, agonists for TLRs that were not expressed by langerin⁺ CD8α⁺ DCs failed to enhance T cell responses. The langerin⁺ CD8α⁺ DCs were shown to be located in the marginal zone of the spleen, where they could readily screen the blood for antigens, and their function was critical to the induction of CD8⁺ T cell responses within six hours of antigen delivery. Interestingly, other local langerin-negative antigen presenting cells (APCs) were shown to be capable of cross-presentation, but with significantly reduced capacity to prime CD8⁺ T cell responses. Therefore, in the second section of this thesis the hypothesis that the langerin-negative APCs were capable of contributing to CD8⁺ T cell responses with appropriately timed stimuli was investigated. One of the downstream effects of inducing NKT cell activation at the time of priming was shown to be the “pre-conditioning” of langerin-negative DCs, allowing them to respond strongly to subsequent TLR ligation. Using SiglecH-DTR mice, it was shown that plasmacytoid DCs (which are langerin-negative) were pre-conditioned by NKT cell activation, allowing them to respond more actively to the delayed TLR stimulation by producing significantly enhanced levels of IFN-α. This factor was also potentially responsible for “feeding back” to the CD8α⁺ DCs (including langerin-expressing CD8α⁺ DCs), to enhance their function, as indicated by increases in cytokine production. Significantly, the major langerin-negative DC populations, defined as CD8α⁻ DCs, were pre-conditioned to have an enhanced cytokine release response to subsequent stimulation through TLR7, a receptor not expressed by langerin-positive DCs. This enhanced ability to respond to TLR7 ligation permitted these langerin-negative APCs to contribute to increased CD8⁺ T cell accumulation, with enhanced functional activity. Importantly, the CD8⁺ T cell response induced remained significantly dependent on initial cross-priming by langerin⁺ CD8α⁺ DCs, and it was only through pre-conditioning that langerinnegative APCs could contribute to enhancing the T cell response. In the third section of this thesis, the hypothesis that the CD8⁺ T cell responses generated in the presence of langerin⁺ CD8α⁺ DCs were phenotypically and functionally distinct from those responses generated in their absence was tested. No obvious differences were seen in CD8⁺ T cell homing, memory phenotype, restimulatory capacity, and expression of key molecules involved in metabolic function, survival and cytolytic function. However, in vivo cytotoxic function several weeks after priming was comparable, suggesting that this function was not related to initial burst size, providing some evidence of difference in function between CD8⁺ T cells primed in the presence or absence of langerin⁺ CD8α⁺ DCs. In summary, the splenic langerin⁺ CD8α⁺ DCs are the major subset responsible for cross-priming CD8⁺ T cell responses to circulating antigen, and for interpreting multiple stimulatory signals for enhancing the response. However, effective CD8⁺ T cell responses can be generated in their absence, particularly when antigens are provided in the context of appropriately temporally phased stimuli.</p>

scholarly journals Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

2005 ◽  
Vol 79 (15) ◽  
pp. 9419-9429 ◽  
Author(s):  
Nicole E. Miller ◽  
Jennifer R. Bonczyk ◽  
Yumi Nakayama ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

scholarly journals Protection against Vaccinia Virus Challenge by CD8 Memory T Cells Resolved by Molecular Mimicry

2006 ◽  
Vol 81 (2) ◽  
pp. 934-944 ◽  
Author(s):  
Markus Cornberg ◽  
Brian S. Sheridan ◽  
Frances M. Saccoccio ◽  
Michael A. Brehm ◽  
Liisa K. Selin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccinia Virus ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Molecular Mimicry ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Epitopes ◽  
Cell Responses

ABSTRACT Live vaccinia virus (VV) vaccination has been highly successful in eradicating smallpox. However, the mechanisms of immunity involved in mediating this protective effect are still poorly understood, and the roles of CD8 T-cell responses in primary and secondary VV infections are not clearly identified. By applying the concept of molecular mimicry to identify potential CD8 T-cell epitopes that stimulate cross-reactive T cells specific to lymphocytic choriomeningitis virus (LCMV) and VV, we identified after screening only 115 peptides two VV-specific immunogenic epitopes that mediated protective immunity against VV. An immunodominant epitope, VV-e7r130, did not generate cross-reactive T-cell responses to LCMV, and a subdominant epitope, VV-a11r198, did generate cross-reactive responses to LCMV. Infection with VV induced strong epitope-specific responses which were stable into long-term memory and peaked at the time virus was cleared, consistent with CD8 T cells assisting in the control of VV. Two different approaches, direct adoptive transfer of VV-e7r-specific CD8 T cells and prior immunization with a VV-e7r-expressing ubiquitinated minigene, demonstrated that memory CD8 T cells alone could play a significant role in protective immunity against VV. These studies suggest that exploiting cross-reactive responses between viruses may be a useful tool to complement existing technology in predicting immunogenic epitopes to large viruses, such as VV, leading to a better understanding of the role CD8 T cells play during these viral infections.

scholarly journals Adrenergic signaling controls early transcriptional programs during CD8+ T cell responses to viral infection

2021 ◽  
Author(s):  
Leonardo Estrada ◽  
Didem Agac Cobanoglu ◽  
Aaron Wise ◽  
Robert Maples ◽  
Murat Can Cobanoglu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Receptor Activation ◽  
Cell Development ◽  
Primary Response ◽  
Cell Responses

Viral infections drive the expansion and differentiation of responding CD8+ T cells into variegated populations of cytolytic effector and memory cells. While pro-inflammatory cytokines and cell surface immune receptors play a key role in guiding T cell responses to infection, T cells are also markedly influenced by neurotransmitters. Norepinephrine is a key sympathetic neurotransmitter, which acts to suppress CD8 + T cell cytokine secretion and lytic activity by signaling through the beta2-adrenergic receptor (ADRB2). Although ADRB2 signaling is considered generally immunosuppressive, its role in regulating differentiation of effector T cells in response to infection has not been investigated. Using an adoptive transfer approach, we compared the expansion and differentiation of wild type (WT) to Adrb2-/- CD8 + T cells throughout the primary response to vesicular stomatitis virus (VSV) infection in vivo. We measured the dynamic changes in transcriptome profiles of antigen-specific CD8 + T cells as they responded to VSV. Within the first 7 days of infection, WT cells out-paced the expansion of Adrb2-/- cells, which correlated with reduced expression of IL-2 and the IL-2Ralpha; in the absence of ADRB2. RNASeq analysis identified over 300 differentially expressed genes that were both temporally regulated following infection and selectively regulated in WT vs Adrb2-/- cells. These genes contributed to major transcriptional pathways including cytokine receptor activation, signaling in cancer, immune deficiency, and neurotransmitter pathways. By parsing genes within groups that were either induced or repressed over time in response to infection, we identified three main branches of genes that were differentially regulated by the ADRB2. These gene sets were predicted to be regulated by specific transcription factors involved in effector T cell development, such as Tbx21 and Eomes. Collectively, these data demonstrate a significant role for ADRB2 signaling in regulating key transcriptional pathways during CD8 + T cells responses to infection that may dramatically impact their functional capabilities and downstream memory cell development.

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