scholarly journals Benign lymph node microenvironment is associated with response to immunotherapy

2020 ◽  
Vol 3 (1) ◽  
pp. 44-53 ◽  
Author(s):  
Maria I Toki ◽  
Deepika Kumar ◽  
Fahad S Ahmed ◽  
David L Rimm ◽  
Mina L Xu
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Immune Checkpoint Blockade ◽  
Splenic Tissue ◽  
Proliferation Index ◽  
Lymphoid Tissues ◽  
Activated T Cells ◽  
Significant Difference ◽  
Benign Lymph Node

Abstract Introduction Benign lymph nodes have been considered the hubs of immune surveillance in cancer patients. The microenvironment of these lymphoid tissues can be immune suppressed, hence allowing for tumor progression. Understanding the spectrum of benign findings in bystander lymph nodes in immune checkpoint blockade therapy could prove to be key to understanding the mechanism and assessing treatment response. Methods Benign lymph nodes and spleen were evaluated from patients treated with immunotherapy who subsequently received postmortem examination. We used quantitative immunofluorescence (QIF) to assess tumor infiltrating lymphocytes (TIL) and macrophage marker expression and characterized activation status using a novel multiplexed QIF assay including CD3, GranzymeB, and Ki67. We performed immunohistochemistry to correlate results of QIF. Results Benign lymph nodes from non-responders to immunotherapy showed significantly higher expression of cytotoxic markers and proliferation index (Ki67) in T cells compared to responders. Higher expression of PD-L1 in macrophages was also observed. There was no significant difference in CD3+ expression, but higher levels of CD8+ T cells as well as CD20+ B cells were seen in lymph nodes of non-responders. No significant differences were seen between responder and non-responder splenic tissue. Findings were supported by traditional immunostaining methods. Conclusions While most studies in biomarkers for immunotherapy focus on tumor microenvironment, we show that benign lymph node microenvironment may predict response to immunotherapy. In responding patients, bystander lymph nodes appear to have been mobilized, resulting in reduced cytotoxic T cells. Conversely, patients whose disease progressed on immunotherapy demonstrate higher levels of macrophages that express increased PD-L1, and activated T cells not recruited to the tumor site.

scholarly journals In situ immunologic characterization of cellular constituents in lymph nodes and spleens involved by Hodgkin's disease

Blood ◽  
1982 ◽  
Vol 59 (2) ◽  
pp. 226-232 ◽  
Author(s):  
S Poppema ◽  
AK Bhan ◽  
EL Reinherz ◽  
MR Posner ◽  
SF Schlossman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Cytotoxic T Cells ◽  
Lymphoid Tissues ◽  
Immunoperoxidase Technique ◽  
Activated T Cells ◽  
Cytoplasmic Staining

The cellular constituents in lymph nodes and spleens of patients with Hodgkin's disease were studied with a series of monoclonal antibodies directed against human thymocyte, peripheral T-cell, and la antigens. Utilizing both an immunoperoxidase technique on frozen tissue sections and indirect immunofluorescence on cell suspensions, wer found that a majority of lymphocytes were T cells, since they stained with anti-T1 and anti-T3 antibodies, which react with all peripheral T cells. In addition, most of these cells were reactive with anti-T4 antibody, which defines the helper/inducer T-cell population, whereas only a minority of cells stained with anti-T5 and anti-T8 antibodies, which are reactive with suppressor/cytotoxic T cells. Moreover, a large proportion of T cells expressed T10 antigen, which is found on activated T cells. A minority of the T cells also expressed la antigen(s), again suggesting that some of the T cells are activated. In contrast, the Reed-sternberg cells did not react with any of these anti- T-cell antibodies or with anti-IgM antiserum, but displayed strong membrane and cytoplasmic staining with anti-la antibody. Taken together, these findings suggest that Reed-Sternberg cells are not of T- cell lineage but may be derived from antigen-presenting reticulum cells in the thymus-dependent areas of lymphoid tissues; these cells are normally associated with T4+ cells.

scholarly journals In situ immunologic characterization of cellular constituents in lymph nodes and spleens involved by Hodgkin's disease

Blood ◽  
1982 ◽  
Vol 59 (2) ◽  
pp. 226-232 ◽  
Author(s):  
S Poppema ◽  
AK Bhan ◽  
EL Reinherz ◽  
MR Posner ◽  
SF Schlossman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Cytotoxic T Cells ◽  
Lymphoid Tissues ◽  
Immunoperoxidase Technique ◽  
Activated T Cells ◽  
Cytoplasmic Staining

Abstract The cellular constituents in lymph nodes and spleens of patients with Hodgkin's disease were studied with a series of monoclonal antibodies directed against human thymocyte, peripheral T-cell, and la antigens. Utilizing both an immunoperoxidase technique on frozen tissue sections and indirect immunofluorescence on cell suspensions, wer found that a majority of lymphocytes were T cells, since they stained with anti-T1 and anti-T3 antibodies, which react with all peripheral T cells. In addition, most of these cells were reactive with anti-T4 antibody, which defines the helper/inducer T-cell population, whereas only a minority of cells stained with anti-T5 and anti-T8 antibodies, which are reactive with suppressor/cytotoxic T cells. Moreover, a large proportion of T cells expressed T10 antigen, which is found on activated T cells. A minority of the T cells also expressed la antigen(s), again suggesting that some of the T cells are activated. In contrast, the Reed-sternberg cells did not react with any of these anti- T-cell antibodies or with anti-IgM antiserum, but displayed strong membrane and cytoplasmic staining with anti-la antibody. Taken together, these findings suggest that Reed-Sternberg cells are not of T- cell lineage but may be derived from antigen-presenting reticulum cells in the thymus-dependent areas of lymphoid tissues; these cells are normally associated with T4+ cells.

scholarly journals Differential T Cell Function and Fate in Lymph Node and Nonlymphoid Tissues

2002 ◽  
Vol 195 (3) ◽  
pp. 317-326 ◽  
Author(s):  
Nicola L. Harris ◽  
Victoria Watt ◽  
Franca Ronchese ◽  
Graham Le Gros
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Lymph Nodes ◽  
Cell Function ◽  
Activated T Cells ◽  
Peripheral Tissues ◽  
Cell Immunity ◽  
Effector Cytokines

The functions and fate of antigen-experienced T cells isolated from lymph node or nonlymphoid tissues were analyzed in a system involving adoptive transfer of in vitro–activated T cells into mice. Activated T cells present in the lymph nodes could be stimulated by antigen to divide, produce effector cytokines, and migrate to peripheral tissues. By contrast, activated T cells that had migrated into nonlymphoid tissues (lung and airway) produced substantial effector cytokines upon antigen challenge, but were completely unable to divide or migrate back to the lymph nodes. Therefore, activated T cells can undergo clonal expansion in the lymph node, but are recruited and retained as nondividing cells in nonlymphoid tissues. These distinct regulatory events in lymph node and nonlymphoid tissues reveal simple key mechanisms for both inducing and limiting T cell immunity.

scholarly journals The Level of Virus-Specific T-Cell and Macrophage Recruitment in Porcine Reproductive and Respiratory Syndrome Virus Infection in Pigs Is Independent of Virus Load

2004 ◽  
Vol 78 (11) ◽  
pp. 5923-5933 ◽  
Author(s):  
Zhengguo Xiao ◽  
Laura Batista ◽  
Scott Dee ◽  
Patrick Halbur ◽  
Michael P. Murtaugh
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Persistent Infection ◽  
T Cell Response ◽  
Growing Pigs ◽  
Respiratory Syndrome Virus ◽  
Lymphoid Tissues ◽  
Virus Load ◽  
Significant Difference

ABSTRACT Porcine reproductive and respiratory syndrome virus (PRRSV) is the most important infectious disease agent of pigs worldwide, causing reproductive failure in pregnant sows and respiratory problems in nursing and growing pigs. PRRSV infection is characterized by a prolonged viremia of 30 or more days and an extended persistent infection of lymphoid tissues. To better understand the immunological basis for prolonged acute and persistent PRRSV infection, we have examined the cell-mediated immune (CMI) response throughout the course of infection and compared the results to the local distribution and abundance of PRRSV in infected tissues. PRRSV-specific T cells, enumerated by gamma interferon enzyme-linked immunospot assay, did not appear until 2 weeks after PRRSV inoculation, and their abundance exhibited substantial variation over time and among animals. In all cases the T-cell response was transient. High levels of viral RNA were present in lymphoid tissues of all animals in the acute phase of infection. Viral loads were decreased 1,000-fold or more in persistent infections, with the primary sites of persistence being tonsil, sternal lymph node, and inguinal lymph node. The abundance of virus-specific T cells in either acutely or persistently infected animals was highly variable and showed no correlation to the level of virus in lymphoid tissues. No significant difference in antigen-specific T-cell abundance was observed in secondary lymphoid tissues in either acute or persistent infection except for tonsil, in which the number of responding cells was extremely low. CD4+- and CD8+-T-cell frequencies did not change after PRRSV infection, though a decrease in γδ T cells was observed. Macrophages, the permissive cell type for PRRSV, were present in various levels in all tissue preparations and were not in proportion to local virus load. These findings indicate that a weak CMI response contributes to prolonged PRRSV infection and suggests that PRRSV suppresses T-cell recognition of infected macrophages. Thus, the slow but eventual resolution of PRRSV infection may be dependent on limiting permissive macrophages and on innate immune factors.

scholarly journals The chemokine SLC is expressed in T cell areas of lymph nodes and mucosal lymphoid tissues and attracts activated T cells via CCR7

1998 ◽  
Vol 28 (6) ◽  
pp. 2025-2034 ◽  
Author(s):  
Katharina Willimann ◽  
Daniel F. Legler ◽  
Marcel Loetscher ◽  
Regula Stuber Roos ◽  
Maria Belen Delgado ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Lymphoid Tissues ◽  
Activated T Cells

Activation of nuclear factor of activated T cells 5 in the peritoneal membrane of uremic patients

2015 ◽  
Vol 308 (11) ◽  
pp. F1247-F1258 ◽  
Author(s):  
Daniel Kitterer ◽  
Joerg Latus ◽  
Christoph Ulmer ◽  
Peter Fritz ◽  
Dagmar Biegger ◽  
...  
Keyword(s):  
T Cells ◽  
Mrna Expression ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Significant Difference ◽  
Ccl2 Mrna ◽  
Uremic Patients ◽  
High Concentrations

Peritoneal inflammation and fibrosis are responses to the uremic milieu and exposure to hyperosmolar dialysis fluids in patients on peritoneal dialysis. Cells respond to high osmolarity via the transcription factor nuclear factor of activated T cells (NFAT5). In the present study, the response of human peritoneal fibroblasts to glucose was analyzed in vitro. Expression levels of NFAT5 and chemokine (C-C motif) ligand (CCL2) mRNA were quantified in peritoneal biopsies of five nonuremic control patients, five uremic patients before PD (pPD), and eight patients on PD (oPD) using real-time PCR. Biopsies from 5 control patients, 25 pPD patients, and 25 oPD patients were investigated using immunohistochemistry to detect the expression of NFAT5, CCL2, NF-κB p50, NF-κB p65, and CD68. High glucose concentrations led to an early, dose-dependent induction of NFAT5 mRNA in human peritoneal fibroblasts. CCL2 mRNA expression was upregulated by high concentrations of glucose after 6 h, but, most notably, a concentration-dependent induction of CCL2 was present after 96 h. In human peritoneal biopsies, NFAT5 mRNA levels were increased in uremic patients compared with nonuremic control patients. No significant difference was found between the pPD group and oPD group. CCL2 mRNA expression was higher in the oPD group. Immunohistochemistry analysis was consistent with the results of mRNA analysis. CD68-positive cells were significantly increased in the oPD group. In conclusion, uremia results in NFAT5 induction, which might promote early changes of the peritoneum. Upregulation of NFAT5 in PD patients is associated with NFκB induction, potentially resulting in the recruitment of macrophages.

scholarly journals A cell-extrinsic ligand acquired by activated T cells in lymph node can bridge L-selectin and P-selectin

PLoS ONE ◽  
2018 ◽  
Vol 13 (10) ◽  
pp. e0205685 ◽  
Author(s):  
Douglas A. Carlow ◽  
Michelle C. Tra ◽  
Hermann J. Ziltener
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Activated T Cells ◽  
A Cell

scholarly journals Normative data for flow cytometry immunophenotyping of benign lymph nodes sampled by surgical biopsy

2017 ◽  
Vol 71 (2) ◽  
pp. 174-179 ◽  
Author(s):  
Gregory David Scott ◽  
Susan K Atwater ◽  
Dita A Gratzinger
Keyword(s):  
Flow Cytometry ◽  
Lymph Node ◽  
T Cell ◽  
Lymph Nodes ◽  
Inflammatory Disease ◽  
Clinical History ◽  
Surgical Biopsy ◽  
Data Set ◽  
Flow Cytometry Data ◽  
Benign Lymph Node

AimsTo create clinically relevant normative flow cytometry data for understudied benign lymph nodes and characterise outliers.MethodsClinical, histological and flow cytometry data were collected and distributions summarised for 380 benign lymph node excisional biopsies. Outliers for kappa:lambda light chain ratio, CD10:CD19 coexpression, CD5:CD19 coexpression, CD4:CD8 ratios and CD7 loss were summarised for histological pattern, concomitant diseases and follow-up course.ResultsWe generated the largest data set of benign lymph node immunophenotypes by an order of magnitude. B and T cell antigen outliers often had background immunosuppression or inflammatory disease but did not subsequently develop lymphoma.ConclusionsDiagnostic immunophenotyping data from benign lymph nodes provide normative ranges for clinical use. Outliers raising suspicion for B or T cell lymphoma are not infrequent (26% of benign lymph nodes). Caution is indicated when interpreting outliers in the absence of excisional biopsy or clinical history, particularly in patients with concomitant immunosuppression or inflammatory disease.

CD4+ T cells are essential for the development of destructive thyroiditis induced by anti–PD-1 antibody in thyroglobulin-immunized mice

2021 ◽  
Vol 13 (593) ◽  
pp. eabb7495
Author(s):  
Yoshinori Yasuda ◽  
Shintaro Iwama ◽  
Daisuke Sugiyama ◽  
Takayuki Okuji ◽  
Tomoko Kobayashi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Mononuclear Cells ◽  
Critical Role ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Histopathological Analysis ◽  
Activated T Cells ◽  
Cervical Lymph Nodes

Immune-related adverse events induced by anti–programmed cell death–1 antibodies (PD-1-Ab), including destructive thyroiditis (thyroid-irAE), are thought to be caused by activated T cells. However, the T cell subsets that are directly responsible for damaging self-organs remain unclear. To clarify which T cell subsets are involved in the development of thyroid-irAE, a mouse model of thyroid-irAE was analyzed. PD-1-Ab administration 2.5 months after immunization with thyroglobulin caused destructive thyroiditis. Thyroiditis was completely prevented by previous depletion of CD4+ T cells and partially prevented by depleting CD8+ T cells. The frequencies of central and effector memory CD4+ T cell subsets and the secretion of interferon-γ after stimulation with thyroglobulin were increased in the cervical lymph nodes of mice with thyroid-irAE compared with controls. Histopathological analysis revealed infiltration of CD4+ T cells expressing granzyme B in thyroid glands and major histocompatibility complex class II expression on thyrocytes in mice with thyroid-irAE. Adoptive transfer of CD4+ T cells from cervical lymph nodes in mice with thyroid-irAE caused destruction of thyroid follicular architecture in the irradiated recipient mice. Flow cytometric analyses showed that the frequencies of central and effector memory CD4+ T cells expressing the cytotoxic marker CD27 were higher in peripheral blood mononuclear cells collected from patients with thyroid-irAE induced by PD-1-Ab versus those without. These data suggest a critical role for cytotoxic memory CD4+ T cells activated by PD-1-Ab in the pathogenesis of thyroid-irAE.

scholarly journals Intravenous Arginine Administration Benefits CD4+ T-Cell Homeostasis and Attenuates Liver Inflammation in Mice with Polymicrobial Sepsis

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1047
Author(s):  
Chiu-Li Yeh ◽  
Sharon Angela Tanuseputero ◽  
Jin-Ming Wu ◽  
Yi-Ru Tseng ◽  
Po-Jen Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Single Dose ◽  
Lymph Node ◽  
T Cell ◽  
Lymph Nodes ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Liver Inflammation ◽  
Aortic Lymph Node ◽  
Inos Inhibitor

This study investigated the effects of a single dose of arginine (Arg) administration at the beginning of sepsis on CD4+ T-cell regulation and liver inflammation in C57BL/6J mice. Mice were divided into normal control (NC), sham (SH), sepsis saline (SS), and sepsis Arg (SA) groups. An inducible nitric oxide (NO) synthase (iNOS) inhibitor was administered to additional sepsis groups to evaluate the role of NO during sepsis. Sepsis was induced using cecal ligation and puncture (CLP). The SS and SA groups received saline or Arg (300 mg/kg body weight) via tail vein 1 h after CLP. Mice were euthanized at 12 and 24 h post-CLP. Blood, para-aortic lymph nodes, and liver tissues were collected for further measurement. The findings showed that sepsis resulted in decreases in blood and para-aortic lymph node CD4+ T-cell percentages, whereas percentages of interleukin (IL)-4- and IL-17-expressing CD4+ T cells were upregulated. Compared to the SS group, Arg administration resulted in maintained circulating and para-aortic lymph node CD4+ T cells, an increased Th1/Th2 ratio, and a reduced Th17/Treg ratio post-CLP. In addition, levels of plasma liver injury markers and expression of inflammatory genes in liver decreased. These results suggest that a single dose of Arg administered after CLP increased Arg availability, sustained CD4+ T-cell populations, elicited more-balanced Th1/Th2/Th17/Treg polarization in the circulation and the para-aortic lymph nodes, and attenuated liver inflammation in sepsis. The favorable effects of Arg were abrogated when an iNOS inhibitor was administered, which indicated that NO may be participated in regulating the homeostasis of Th/Treg cells and subsequent liver inflammation during sepsis.

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