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  • 1
    Online Resource
    Online Resource
    Resident memory CD8+ T cells in regional lymph nodes mediate immunity to metastatic melanoma
    Elsevier BV ; 2021
    In:  Immunity Vol. 54, No. 9 ( 2021-09), p. 2117-2132.e7
    Details
    In: Immunity, Elsevier BV, Vol. 54, No. 9 ( 2021-09), p. 2117-2132.e7
    Type of Medium: Online Resource
    ISSN: 1074-7613
    URL: Article
    DOI: 10.1016/j.immuni.2021.08.019
    RVK:
    XA 48754.8
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 1217235-2
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  • 2
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    PD-L1 blockade enhances brain resident memory T cell function and stimulates brain to lymph node crosstalk
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 59.20-59.20
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 59.20-59.20
    Abstract: Resident memory T cells (T RM) are a unique subset of memory T cells that persist within non-lymphoid tissues. Previous studies have identified T RMwithin the brain (bT RM) after peripheral infection and vaccination in mice, with more recent appreciation in human brain tissue. While bT RMare important for protection of the CNS against reinfection, their heterogeneity at the single cell level and overall involvement in shaping the neuroimmune landscape remains unknown. Here, we defined viral-specific bT RMheterogeneity by single cell RNA sequencing and identified unique subsets dependent on local antigen encounter. These data also confirmed previous findings that bT RMexpress markers associated with T cell exhaustion, such as PD-1. Despite this, intracranial delivery of cognate viral peptide led to robust bT RMreactivation and initiated a cascade of immune activation and accumulation within the brain, including rapid activation of microglia, NK cells and T cells, DC maturation, and infiltration of macrophages and monocyte derived DCs. In the presence of PD-L1 blockade, despite observing higher effector molecule production from reactivated bT RM, we found no apparent difference in downstream immune activation in the brain. Interestingly, however, we found a significant increase in DC and B cell maturation in the CNS draining deep cervical lymph nodes (dcLN) only in the presence of PD-L1 blockade. These data indicate a potential unique crosstalk between bT RMand APCs in the dcLN normally suppressed by PD-1/PD-L1 signaling. These studies provide insight into brain T RMfunctions and potential mechanisms for strengthening immune activation that can guide immunotherapies for immunologically cold brain tumors. Supported by grants from the NIH (K22AI148508-02, T32 AI007363)
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.59.20
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
    detail.hit.zdb_id: 3056-9
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  • 3
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    CD39 Is Expressed on Functional Effector and Tissue-resident Memory CD8+ T Cells
    The American Association of Immunologists ; 2024
    In:  The Journal of Immunology ( 2024-07-08)
    Details
    In: The Journal of Immunology, The American Association of Immunologists, ( 2024-07-08)
    Abstract: The ecto-ATPase CD39 is expressed on exhausted CD8+ T cells in chronic viral infection and has been proposed as a marker of tumor-specific CD8+ T cells in cancer, but the role of CD39 in an effector and memory T cell response has not been clearly defined. We report that CD39 is expressed on Ag-specific CD8+ short-lived effector cells, while it’s co-ectoenzyme, CD73, is found on memory precursor effector cells (MPECs) in vivo. Inhibition of CD39 enzymatic activity during in vitro T cell priming enhances MPEC differentiation in vivo after transfer and infection. The enriched MPEC phenotype is associated with enhanced tissue resident memory T cell (TRM cell) establishment in the brain and salivary gland following an acute intranasal viral infection, suggesting that CD39 ATPase activity plays a role in memory CD8+ T cell differentiation. We also show that CD39 is expressed on human and murine TRM cells across several nonlymphoid tissues and melanoma, whereas CD73 is expressed on both circulating and resident memory subsets in mice. In contrast to exhausted CD39+ T cells in chronic infection, CD39+ TRM cells are fully functional when stimulated ex vivo with cognate Ag, further expanding the identity of CD39 beyond a T cell exhaustion marker.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2400151
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2024
    detail.hit.zdb_id: 1475085-5
    detail.hit.zdb_id: 3056-9
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  • 4
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    Brain resident memory CD8+ T cells trigger CNS immune activation and infiltration
    The American Association of Immunologists ; 2022
    In:  The Journal of Immunology Vol. 208, No. 1_Supplement ( 2022-05-01), p. 165.18-165.18
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 208, No. 1_Supplement ( 2022-05-01), p. 165.18-165.18
    Abstract: The shifting paradigm regarding immune surveillance of the central nervous system (CNS) has shed light on immune cell networks thought to be absent from healthy brain tissue. Resident memory T cells (TRM) are a unique subset of memory T cells that persist within non-lymphoid tissues to provide rapid onset protection against reinfection. Recently, brain TRM (bTRM) have been identified in humans, with CNS or peripheral infection, or vaccination leading to bTRM establishment in mice. While bTRM are important for protection of the CNS against reinfection, their regulation and involvement in shaping the neuroimmune landscape remains unknown. Here, we take a reductionist approach employing viral-derived peptides to show that CD8+ bTRM reactivation is sufficient to initiate a cascade of innate and adaptive immune activation in the brain. Specifically, bTRM reactivation triggered activation of NK cells, T cells, microglia, and induced dendritic cell (DC) maturation, including upregulation of lymph node homing molecules. Reactivated bTRM also promoted accumulation of DCs in draining lymph nodes, and macrophages, monocyte-derived DCs, T cells and NK cells in the brain. Our preliminary data suggests that PD-1:PD-L1 signaling regulates the magnitude of this response, as PD-L1 blockade led to enhanced bTRM activation and neuroinflammation. We anticipate our results to illuminate roles for PD-1 signaling on bTRM in the context of pathogen clearance, and neurologic toxicities seen in cancer patients following PD-1 inhibitor treatment. This study will also provide insight into the pathologic or protective capacity of bTRM in neurologic diseases where T cells are implicated, such as Alzheimer’s disease, multiple sclerosis, and brain cancer. Supported by grants from NIH (K22 AI148508-02, T32 AI007363)
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.208.Supp.165.18
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2022
    detail.hit.zdb_id: 1475085-5
    detail.hit.zdb_id: 3056-9
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  • 5
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    Validation of Ligand Tetramers for the Detection of Antigen-Specific Lymphocytes
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 8 ( 2023-04-15), p. 1156-1165
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 8 ( 2023-04-15), p. 1156-1165
    Abstract: The study of Ag-specific lymphocytes has been a key advancement in immunology over the past few decades. The development of multimerized probes containing Ags, peptide:MHC complexes, or other ligands was one innovation allowing the direct study of Ag-specific lymphocytes by flow cytometry. Although these types of study are now common and performed by thousands of laboratories, quality control and assessment of probe quality are often minimal. In fact, many of these types of probe are made in-house, and protocols vary between laboratories. Although peptide:MHC multimers can often be obtained from commercial sources or core facilities, few such services exist for Ag multimers. To ensure high quality and consistency with ligand probes, we have developed an easy and robust multiplexed approach using commercially available beads able to bind Abs specific for the ligand of interest. Using this assay, we have sensitively assessed the performance of peptide:MHC and Ag tetramers and have found considerable batch-to-batch variability in performance and stability over time more easily than using murine or human cell-based assays. This bead-based assay can also reveal common production errors such as miscalculation of Ag concentration. This work could set the stage for the development of standardized assays for all commonly used ligand probes to limit laboratory-to-laboratory technical variation and experimental failure caused by probe underperformance.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2200934
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
    detail.hit.zdb_id: 3056-9
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  • 6
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    Temporal requirements for TGF-β and IL-7 in generating resident memory T cell responses to melanoma
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 171.14-171.14
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 171.14-171.14
    Abstract: Resident memory CD8 +(T RM) cells persist in tissues and are critical mediators of the host anti-tumor response. We previously demonstrated that protective, melanoma/melanocyte antigen-specific CD8 +T RMcells are generated in skin and B16 tumor-draining lymph nodes (LNs) of mice following CD4 +T cell depletion and tumor excision surgery. Whereas TGF-β and IL-7 have previously been shown to play important roles in generating viral Ag-specific T RMcells, a role for these cytokines in generating T RMresponses against tumor antigens had not been studied. We employed antibody-mediated blockade of TGF-β (mAb clone 1D11.16.8) or IL-7 receptor (IL-7R; mAb clone A7R34) during primary tumor growth or after tumor excision to define a temporal role for these cytokines in generating the T RMresponse. Sentinel gp100-specific pmel CD8 +T cells were used to monitor priming and memory generation. TGF-β blockade during tumor growth did not impair primary responses but significantly reduced CD103 +CD69 +T RMformation in skin and draining LNs one month later. TGF-β signaling was only required during priming, as delayed blockade after tumor excision had no effect. Conversely, IL-7R blockade during priming did not impair T RMgeneration in skin or LN. However, its blockade after tumor excision significantly impaired T RMformation in both locations. These studies demonstrate temporally distinct requirements for TGF-β and IL-7 in promoting T RMresponses against tumor antigens. Supported by grants from the NIH (R01CA22502, T32-AI007363), The Knights of the York Cross of Honour and O. Ross McIntyre, M.D. Endowment to MJT
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.171.14
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
    detail.hit.zdb_id: 3056-9
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  • 7
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    The Effect of Lung Resection for NSCLC on Circulating Immune Cells: A Pilot Study
    MDPI AG ; 2023
    In:  Current Oncology Vol. 30, No. 5 ( 2023-05-17), p. 5116-5134
    Details
    In: Current Oncology, MDPI AG, Vol. 30, No. 5 ( 2023-05-17), p. 5116-5134
    Abstract: This pilot study sought to evaluate the circulating levels of immune cells, particularly regulatory T-cell (Treg) subsets, before and after lung resection for non-small cell lung cancer. Twenty-five patients consented and had specimens collected. Initially, peripheral blood of 21 patients was collected for circulating immune cell studies. Two of these patients were excluded due to technical issues, leaving 19 patients for the analyses of circulating immune cells. Standard gating and high-dimensional unsupervised clustering flow cytometry analyses were performed. The blood, tumors and lymph nodes were analyzed via single-cell RNA and TCR sequencing for Treg analyses in a total of five patients (including four additional patients from the initial 21 patients). Standard gating flow cytometry revealed a transient increase in neutrophils immediately following surgery, with a variable neutrophil–lymphocyte ratio and a stable CD4–CD8 ratio. Unexpectedly, the total Treg and Treg subsets did not change with surgery with standard gating in short- or long-term follow-up. Similarly, unsupervised clustering of Tregs revealed a dominant cluster that was stable perioperatively and long-term. Two small FoxP3hi clusters slightly increased following surgery. In the longer-term follow-up, these small FoxP3hi Treg clusters were not identified, indicating that they were likely a response to surgery. Single-cell sequencing demonstrated six CD4+FoxP3+ clusters among the blood, tumors and lymph nodes. These clusters had a variable expression of FoxP3, and several were mainly, or only, present in tumor and lymph node tissue. As such, serial monitoring of circulating Tregs may be informative, but not completely reflective of the Tregs present in the tumor microenvironment.
    Type of Medium: Online Resource
    ISSN: 1718-7729
    URL: Article
    DOI: 10.3390/curroncol30050387
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2270777-3
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  • 8
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    Memory CD8+ T cell responses to cancer
    Elsevier BV ; 2020
    In:  Seminars in Immunology Vol. 49 ( 2020-06), p. 101435-
    Details
    In: Seminars in Immunology, Elsevier BV, Vol. 49 ( 2020-06), p. 101435-
    Type of Medium: Online Resource
    ISSN: 1044-5323
    URL: Article
    DOI: 10.1016/j.smim.2020.101435
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 1018141-6
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  • 9
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    Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy
    Springer Science and Business Media LLC ; 2021
    In:  Nature Cancer Vol. 2, No. 3 ( 2021-03-24), p. 300-311
    Details
    In: Nature Cancer, Springer Science and Business Media LLC, Vol. 2, No. 3 ( 2021-03-24), p. 300-311
    Type of Medium: Online Resource
    ISSN: 2662-1347
    URL: Article
    DOI: 10.1038/s43018-021-00180-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 3005299-3
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  • 10
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    Fluid Optimisation in Emergency Laparotomy (FLO-ELA) Trial: study protocol for a multi-centre randomised trial of cardiac output-guided fluid therapy compared to usual care in patients undergoing major emergency gastrointestinal surgery
    Springer Science and Business Media LLC ; 2023
    In:  Trials Vol. 24, No. 1 ( 2023-05-06)
    Details
    In: Trials, Springer Science and Business Media LLC, Vol. 24, No. 1 ( 2023-05-06)
    Abstract: Postoperative morbidity and mortality in patients undergoing major emergency gastrointestinal surgery are a major burden on healthcare systems. Optimal management of perioperative intravenous fluids may reduce mortality rates and improve outcomes from surgery. Previous small trials of cardiac-output guided haemodynamic therapy algorithms in patients undergoing gastrointestinal surgery have suggested this intervention results in reduced complications and a modest reduction in mortality. However, this existing evidence is based mainly on elective (planned) surgery, with little evaluation in the emergency setting. There are fundamental clinical and pathophysiological differences between the planned and emergency surgical setting which may influence the effects of this intervention. A large definitive trial in emergency surgery is needed to confirm or refute the potential benefits observed in elective surgery and to inform widespread clinical practice. Methods The FLO-ELA trial is a multi-centre, parallel-group, open, randomised controlled trial. 3138 patients aged 50 and over undergoing major emergency gastrointestinal surgery will be randomly allocated in a 1:1 ratio using minimisation to minimally invasive cardiac output monitoring to guide protocolised administration of intra-venous fluid, or usual care without cardiac output monitoring. The trial intervention will be carried out during surgery and for up to 6 h postoperatively. The trial is funded through an efficient design call by the National Institute for Health and Care Research Health Technology Assessment (NIHR HTA) programme and uses existing routinely collected datasets for the majority of data collection. The primary outcome is the number of days alive and out of hospital within 90 days of randomisation. Participants and those delivering the intervention will not be blinded to treatment allocation. Participant recruitment started in September 2017 with a 1-year internal pilot phase and is ongoing at the time of publication. Discussion This will be the largest contemporary randomised trial examining the effectiveness of perioperative cardiac output-guided haemodynamic therapy in patients undergoing major emergency gastrointestinal surgery. The multi-centre design and broad inclusion criteria support the external validity of the trial. Although the clinical teams delivering the trial interventions will not be blinded, significant trial outcome measures are objective and not subject to detection bias. Trial registration ISRCTN 14729158. Registered on 02 May 2017.
    Type of Medium: Online Resource
    ISSN: 1745-6215
    URL: Article
    DOI: 10.1186/s13063-023-07275-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2040523-6
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