Vaccine-Induced Anti-Neuroblastoma Immunity Early after HSCT Arises in the Presence of Foxp3+CD25+CD4+ T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3692-3692
Author(s):  
Weiqing Jing ◽  
Rimas J. Orentas ◽  
Bryon D. Johnson
Keyword(s):  
T Cells ◽  
Adoptive Transfer ◽  
Vaccine Efficacy ◽  
Cd4 T Cells ◽  
Cell Function ◽  
Tumor Vaccine ◽  
Neuroblastoma Cells ◽  
Early Time ◽  
Antibody Treatment ◽  
Induced Immunity

Abstract Effective anti-neuroblastoma immunity can be induced in mice as early as 1 week after syngeneic HSCT by vaccination with neuroblastoma cells transfected to express CD80, CD86, CD54, and CD137L. However, effective vaccination at this early time point also requires adoptive transfer of T cells (2×107 splenocytes). Previous results in non-transplanted mice showed that T-reg depletion/blockade with anti-CD25 mAb (clone PC61) increased tumor vaccine efficacy. To determine if PC61 treatment might be effective early after HSCT, we first determined if CD4+CD25+Foxp3+ T-reg cells were present, derived either from host (i.e., they survived lethal TBI) or from the transferred spleen cells. Even though transferred splenocytes accelerated T cell reconstitution, HSCT recipient mice remained severely lymphopenic until 3 weeks after transplant. Furthermore, the percentage of Foxp3+ cells in the splenic CD4 fraction was significantly increased in transplanted mice, being as much as 3 times higher than that in non-transplanted mice (35% vs. 12%). During this time, the majority of CD25+Foxp3+CD4+ cells were derived from the adoptively-transferred T cells. Despite the presence of CD25+Foxp3+CD4+ T cells, protective anti-tumor immunity could still be efficiently induced. To examine whether depletion/inhibition of CD25+ T-reg cells could further enhance vaccine-induced immunity in transplanted mice, two strategies were tested: (a) physical depletion of CD25+ regulatory T cells from the adoptively-transferred T cells, and (b) anti-CD25 mAb treatment of the transplanted mice 4 days after HSCT to target both transferred and residual endogenous CD25+ cells. Immunomagnetic depletion eliminated more then 95% of the CD25+ T cells in the transferred population, but only 70% of Foxp3+CD4+ T cells. Adoptive transfer of CD25-depleted splenocytes at the time of HSCT resulted in modest increased tumor vaccine efficacy as compared to mice given non-depleted splenocytes. Two weeks after HSCT, both groups of mice contained similar percentages of Foxp3+CD4+ T cells in the blood and lymph nodes, but a lower frequency of Foxp3+CD4+ T cells was detected in the spleens of mice given CD25-depleted splenocytes (35% vs. 43%, p<0.01). Our second strategy, treatment of HSCT recipients with anti-CD25 mAb prior to tumor vaccination, negatively influenced the vaccine-induced anti-tumor response and resulted in decreased survival. This suggested that the antibody treatment inhibited effector cell function in the early post-transplant setting. IFN-γ ELISpot analysis demonstrated that vaccinated transplant recipients given anti-CD25 mAb had significantly decreased numbers of tumor-specific CD4 T cells in spleen. Collectively, these results suggest that anti-neuroblastoma immunity could be induced in the present of CD25+Foxp3+CD4+ T-reg cells early after HSCT; strategies that targeted at CD25 did not significantly increase the efficacy of the tumor vaccine.

Adoptive Transfer of T Cell Help Breaks Tolerance in Endogenous, Tumor-Specific CD8+ T Cells Responding to a Growing Tumor.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3056-3056
Author(s):  
Jie Wang ◽  
Maryam Aalamian ◽  
Sanju Jalla ◽  
Leo Luznik ◽  
Ephraim J. Fuchs
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Tumor Vaccine ◽  
Graft Versus Host Reaction ◽  
Vaccine Administration ◽  
T Cell Help

Abstract Patients who reject allogeneic blood or marrow grafts after non-myeloablative conditioning sometimes develop delayed or sustained clinical disease responses, raising the possibility that a transient graft-versus-host reaction rekindles dormant anti-tumor immunity by recipient T cells. More specifically, we postulate that endogenous tumor-specific CD8+ T cells are not irreversibly tolerant of a growing tumor, and can be activated to effector function by tumor antigen recognition in the presence of adoptively transferred CD4+ T cell help. We have tested this hypothesis by examining the response of influenza hemagglutinin (HA)-specific “endogenous” CD8+ T cells in HA-tumor-bearing mice treated with cyclophosphamide (Cy) and adoptive transfer of allogeneic or tumor-specific CD4+ T cells, with or without concomitant tumor vaccine administration. In these models, this combination therapy induced the clonal expansion of endogenous, tumor-specific CD8+ T cells, their secretion of interferon gamma, and in vivo cytolytic activity against HA-expressing cells. In separate experiments, adoptively transferred, major histocompatibility complex-mismatched CD4+ T cells induced the activation of recipient, CD11c+ dendritic cells, as demonstrated by enhanced expression of the costimulatory molecules CD80 and CD86. The administration of Cy followed by infusion of allogeneic T cells, with or without tumor vaccine administration, also induced regression of B cell leukemia/lymphoma or established prostate cancer. These results highlight the potential cooperation of donor CD4+ T cells and recipient CD8+ T cells in transient or stable mixed hematopoietic chimeras, and open new avenues for the immunotherapy of cancer in the clinic.

scholarly journals Interleukins and Interleukin Receptors Evolutionary History and Origin in Relation to CD4+ T Cell Evolution

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 813
Author(s):  
Norwin Kubick ◽  
Pavel Klimovich ◽  
Patrick Henckell Flournoy ◽  
Irmina Bieńkowska ◽  
Marzena Łazarczyk ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Positive Selection ◽  
Cd4 T Cells ◽  
Cell Function ◽  
Single Gene ◽  
Ancestral Reconstruction ◽  
Critical Function ◽  
Interleukin Receptors

Understanding the evolution of interleukins and interleukin receptors is essential to control the function of CD4+ T cells in various pathologies. Numerous aspects of CD4+ T cells’ presence are controlled by interleukins including differentiation, proliferation, and plasticity. CD4+ T cells have emerged during the divergence of jawed vertebrates. However, little is known about the evolution of interleukins and their origin. We traced the evolution of interleukins and their receptors from Placozoa to primates. We performed phylogenetic analysis, ancestral reconstruction, HH search, and positive selection analysis. Our results indicated that various interleukins' emergence predated CD4+ T cells divergence. IL14 was the most ancient interleukin with homologs in fungi. Invertebrates also expressed various interleukins such as IL41 and IL16. Several interleukin receptors also appeared before CD4+ T cells divergence. Interestingly IL17RA and IL17RD, which are known to play a fundamental role in Th17 CD4+ T cells first appeared in mollusks. Furthermore, our investigations showed that there is not any single gene family that could be the parent group of interleukins. We postulate that several groups have diverged from older existing cytokines such as IL4 from TGFβ, IL10 from IFN, and IL28 from BCAM. Interleukin receptors were less divergent than interleukins. We found that IL1R, IL7R might have diverged from a common invertebrate protein that contained TIR domains, conversely, IL2R, IL4R and IL6R might have emerged from a common invertebrate ancestor that possessed a fibronectin domain. IL8R seems to be a GPCR that belongs to the rhodopsin-like family and it has diverged from the Somatostatin group. Interestingly, several interleukins that are known to perform a critical function for CD4+ T cells such as IL6, IL17, and IL1B have gained new functions and evolved under positive selection. Overall evolution of interleukin receptors was not under significant positive selection. Interestingly, eight interleukin families appeared in lampreys, however, only two of them (IL17B, IL17E) evolved under positive selection. This observation indicates that although lampreys have a unique adaptive immune system that lacks CD4+ T cells, they could be utilizing interleukins in homologous mode to that of the vertebrates' immune system. Overall our study highlights the evolutionary heterogeneity within the interleukins and their receptor superfamilies and thus does not support the theory that interleukins evolved solely in jawed vertebrates to support T cell function. Conversely, some of the members are likely to play conserved functions in the innate immune system.

scholarly journals Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HIV Replication and PD-1 Expression on CD4+ T Cells

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 753
Author(s):  
Mohammad Haque ◽  
Fengyang Lei ◽  
Xiaofang Xiong ◽  
Yijie Ren ◽  
Hao-Yun Peng ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Viral Antigen ◽  
Peritoneal Macrophages ◽  
Hiv Replication ◽  
Specific Ctls ◽  
Immunodeficiency Virus ◽  
Hiv 1

The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression.

scholarly journals CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 580-588 ◽  
Author(s):  
Kathrin Gollmer ◽  
François Asperti-Boursin ◽  
Yoshihiko Tanaka ◽  
Klaus Okkenhaug ◽  
Bart Vanhaesebroeck ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Early Time ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activation Markers

Abstract CD4+ T cells use the chemokine receptor CCR7 to home to and migrate within lymphoid tissue, where T-cell activation takes place. Using primary T-cell receptor (TCR)–transgenic (tg) CD4+ T cells, we explored the effect of CCR7 ligands, in particular CCL21, on T-cell activation. We found that the presence of CCL21 during early time points strongly increased in vitro T-cell proliferation after TCR stimulation, correlating with increased expression of early activation markers. CCL21 costimulation resulted in increased Ras- and Rac-GTP formation and enhanced phosphorylation of Akt, MEK, and ERK but not p38 or JNK. Kinase-dead PI3KδD910A/D910A or PI3Kγ-deficient TCR-tg CD4+ T cells showed similar responsiveness to CCL21 costimulation as control CD4+ T cells. Conversely, deficiency in the Rac guanine exchange factor DOCK2 significantly impaired CCL21-mediated costimulation in TCR-tg CD4+ T cells, concomitant with impaired Rac- but not Ras-GTP formation. Using lymph node slices for live monitoring of T-cell behavior and activation, we found that G protein-coupled receptor signaling was required for early CD69 expression but not for Ca2+ signaling. Our data suggest that the presence of CCL21 during early TCR signaling lowers the activation threshold through Ras- and Rac-dependent pathways leading to increased ERK phosphorylation.

scholarly journals Mucosal immune stimulation with HSV-2 and polyICLC boosts control of viremia in SIVΔNef vaccinated rhesus macaques with breakthrough SIV infection

2020 ◽  
Author(s):  
Meropi Aravantinou ◽  
Olga Mizenina ◽  
Thilo Brill ◽  
Jessica Kenney ◽  
Christine Timmons ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Immune Activation ◽  
Vaccine Efficacy ◽  
Cd4 T Cells ◽  
Hiv Vaccine ◽  
Live Attenuated Vaccine ◽  
Siv Infection ◽  
The Impact

ABSTRACTDevelopment of an effective human immunodeficiency virus (HIV) vaccine is among the highest priorities in the biomedical research agenda. Adjuvants enhance vaccine efficacy, but in the case of HIV, strong or inappropriate immune activation may undermine protection by increasing HIV susceptibility. Co-infection with immunomodulatory pathogens may also impact vaccine efficacy. In the rhesus macaque rectal SIVΔNef live attenuated vaccine model, we utilized a low virulence HSV-2 infection and the double-stranded RNA viral mimic polyICLC as tools to probe the effects of distinct types of immune activation on HIV vaccine efficacy and explore novel correlates of protection from wild type SIV. Rectally administered HSV-2 and polyICLC impacted the protection conferred by mucosal SIVΔNef vaccination by favoring partial protection in animals with breakthrough infection following virulent SIV challenge (“Controllers”). However, SIVΔNef persistence in blood and tissues did not predict protection in this rectal immunization and challenge model. Non-controllers had similar SIVΔNef viremia as completely protected macaques, and while they tended to have less replication competent SIVΔNef in lymph nodes, controllers had no recoverable virus in the lymph nodes. Non-controllers differed from protected macaques immunologically by having a greater frequency of pro-inflammatory CXCR3+CCR6+ CD4 T cells in blood and a monofunctional IFNγ-dominant CD8 T cell response in lymph nodes. Controller phenotype was associated with heightened IFNα production during acute SIV infection and a greater frequency of CXCR5+ CD4 T cells in blood pre-challenge despite a lower frequency of cells with the T follicular helper (Tfh) cell phenotype in blood and lymph nodes. Our results establish novel correlates of immunological control of SIV infection while reinforcing the potential importance of T cell functionality and location in SIVΔNef efficacy. Moreover, this work highlights that triggering of mucosal immunity can aid mucosal vaccine strategies rather than undermine protection.AUTHOR SUMMARYAn efficacious HIV vaccine is essential to contain the HIV pandemic. Vaccine-mediated protection from HIV may be either enhanced or obstructed by mucosal immune activation; thus, the impact of adjuvants and underlying co-infections that lead to immune activation needs to be evaluated. Using the SIV macaque model, we set out to study the impact of underlying infection with HSV-2 or treatment with the adjuvant polyICLC on rectal immunization with the live attenuated vaccine SIVΔNef. We found that neither stimulus impacted complete protection from SIV; however, the combination of HSV-2 and polyICLC improved control of infection in animals that were not completely protected. Compared with non-controller macaques, controllers had less inflammatory T cells before SIV challenge as well as greater gene expression of IFNα and more functional SIV-specific T cells after infection. The results add to our understanding of the mechanisms of SIVΔNef protection and demonstrate that mucosal immune activation does not necessarily undermine protection in mucosal vaccination against HIV.

IL-6 enhances CD4 cell motility by sustaining mitochondrial Ca2+ through the noncanonical STAT3 pathway

2021 ◽  
Vol 118 (37) ◽  
pp. e2103444118
Author(s):  
Felipe Valença-Pereira ◽  
Qian Fang ◽  
Isabelle J. Marié ◽  
Emily L. Giddings ◽  
Karen A. Fortner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Motility ◽  
Cd4 T Cells ◽  
Cell Function ◽  
Inflammatory Diseases ◽  
Cd4 T Cell ◽  
Noncanonical Pathway ◽  
Cd4 Cell ◽  
Intrinsic Effect

Interleukin 6 (IL-6) is known to regulate the CD4 T cell function by inducing gene expression of a number of cytokines through activation of Stat3 transcription factor. Here, we reveal that IL-6 strengthens the mechanics of CD4 T cells. The presence of IL-6 during activation of mouse and human CD4 T cells enhances their motility (random walk and exploratory spread), resulting in an increase in travel distance and higher velocity. This is an intrinsic effect of IL-6 on CD4 T-cell fitness that involves an increase in mitochondrial Ca2+. Although Stat3 transcriptional activity is dispensable for this process, IL-6 uses mitochondrial Stat3 to enhance mitochondrial Ca2+-mediated motility of CD4 T cells. Thus, through a noncanonical pathway, IL-6 can improve competitive fitness of CD4 T cells by facilitating cell motility. These results could lead to alternative therapeutic strategies for inflammatory diseases in which IL-6 plays a pathogenic role.

scholarly journals Functional Tolerance is Maintained Despite Proliferation of CD4 T Cells after Encounter with Tissue-derived Antigen

2002 ◽  
Vol 9 (3) ◽  
pp. 173-176
Author(s):  
Lara J. Ausubel ◽  
Anna Chodos ◽  
Nyree Bekarian ◽  
Abul K. Abbas ◽  
Lucy S. K. Walker
Keyword(s):  
T Cells ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Negative Selection ◽  
Tissue Injury ◽  
The Self ◽  
Transfer System ◽  
Insulin Promoter ◽  
Functional Tolerance ◽  
Peripheral Activation

Since negative selection in the thymus is incomplete, some self-reactive T cells are able to mature and seed the periphery. To study how these T cells interact following encounter with the self-protein they recognize in the periphery, we have developed an adoptive transfer system in which HEL-specific TCR transgenic CD4 T cells are transferred to mice expressing HEL protein in the pancreas under the control of the rat insulin promoter. Here we show that after adoptive transfer of HEL-specific T cells functional tolerance is maintained despite evidence that the T cells encounter and respond to pancreas-expressed antigen. Even the provision of an additional activation stimulus by peripheral immunization with HEL protein is insufficient to induce the T cells to cause autoimmune tissue injury. However, in the presence of blocking anti-CTLA-4-mAb, immunized adoptive transfer recipients rapidly developed diabetes. These data suggest that the CTLA-4 pathway regulates the pathogenicity of antigen-specific T cells following a peripheral activation stimulus.

scholarly journals Borna disease, a progressive meningoencephalomyelitis as a model for CD4+ T cell-mediated immunopathology in the brain.

1989 ◽  
Vol 170 (3) ◽  
pp. 1045-1050 ◽  
Author(s):  
J A Richt ◽  
L Stitz ◽  
H Wekerle ◽  
R Rott
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Mhc Class Ii ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Immune Cell ◽  
Cd4 T Cell ◽  
The Brain ◽  
Borna Disease

A homogeneous T cell line NM1 with Borna disease (BD) virus reactivity could be established. The NM1 cells have been characterized as CD4+ T cells. Adoptive transfer revealed that this MHC class II-restricted immune cell is responsible for the immunopathological effect leading to BD, a progressive meningoencephalomyelitis.

Identification of a Discrete Subpopulation of T-Cells Over-Expressing HDAC11 with a TH17 Phenotype

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 588-588
Author(s):  
Karrune Woan ◽  
Fengdong Cheng ◽  
Hongwei Wang ◽  
Jennifer Rock-Klotz ◽  
Zi Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Function ◽  
Conflicts Of Interest ◽  
Negative Regulator ◽  
Egfp Expression ◽  
In Vivo Models

Abstract Abstract 588 We recently defined a novel role of histone deacetylase 11 (HDAC11), the newest member of the HDAC family, as a negative regulator of IL-10 gene transcription in antigen-presenting cells (APCs).1 To better understand the role of HDAC11 gene expression in immune cells in vivo, we have utilized a BAC (Bacterial artificial chromosome) transgenic mouse in which the EGFP reporter gene was inserted downstream of the HDAC11 promoter region but immediately upstream of the HDAC11 coding sequence (TgHDAC11-EGFP mice).2 In the steady-state, macrophages and B-cells isolated from spleen of TgHDAC11-EGFP mice express low levels of HDAC11 as evidenced by a slight shift in EGFP fluorescence from background. In sharp contrast, we identified a discrete population (11.9%) of T-cells over-expressing HDAC11 as demonstrated both by flow cytometry for EGFP and by qRT-PCR for HDAC11, a majority of which were CD4+ T-cells. Sorting of this EGFP+, CD4+ T-cell population confirmed that the increased EGFP expression correlated with an increased HDAC11mRNA expression. Reminiscent of our prior data in APCs, the increased expression of HDAC11 in T-cells was also inversely correlated with IL-10mRNA expression. Further analyses revealed that in the absence of any stimulation or T-cell polarizing conditions, this EGFP positive population expressed significantly elevated levels of ROR-γt and IL-17 mRNA, markers specific for the TH17 subpopulation. Polarization of wild type CD4+ T-cells into functional TH17 cells was associated with reduction of HDAC11 expression, suggesting a potential role for HDAC11 in regulating T-cell function and/or activation, in particular within the TH17 subset. Further support for this regulatory role of HDAC11 has been provided by our additional findings that T-cells devoid of HDAC11 are indeed hyper-reactive in vitro and in in vivo models. 1. Villagra A, et al. Nat Immunol. 2009 Jan;10(1):92-100. 2. Gong S, et al. Nature. 2003 Oct 30;425(6961):917-25. Disclosures: No relevant conflicts of interest to declare.

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