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 With Minimal Systemic T-Cell Expansion, CD8+ T Cells Mediate Protection of Rhesus Macaques Immunized with Attenuated Simian-Human Immunodeficiency Virus SHIV89.6 from Vaginal Challenge with Simian Immunodeficiency Virus

2008 ◽  
Vol 82 (22) ◽  
pp. 11181-11196 ◽  
Author(s):  
Meritxell Genescà ◽  
Pamela J. Skinner ◽  
Jung Joo Hong ◽  
Jun Li ◽  
Ding Lu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
T Cell Response ◽  
Lymphoid Tissues ◽  
Vaginal Mucosa ◽  
Challenge Virus ◽  
Immunodeficiency Virus

ABSTRACT The presence, at the time of challenge, of antiviral effector T cells in the vaginal mucosa of female rhesus macaques immunized with live-attenuated simian-human immunodeficiency virus 89.6 (SHIV89.6) is associated with consistent and reproducible protection from pathogenic simian immunodeficiency virus (SIV) vaginal challenge (18). Here, we definitively demonstrate the protective role of the SIV-specific CD8+ T-cell response in SHIV-immunized monkeys by CD8+ lymphocyte depletion, an intervention that abrogated SHIV-mediated control of challenge virus replication and largely eliminated the SIV-specific T-cell responses in blood, lymph nodes, and genital mucosa. While in the T-cell-intact SHIV-immunized animals, polyfunctional and degranulating SIV-specific CD8+ T cells were present in the genital tract and lymphoid tissues from the day of challenge until day 14 postchallenge, strikingly, expansion of SIV-specific CD8+ T cells in the immunized monkeys was minimal and limited to the vagina. Thus, protection from uncontrolled SIV replication in animals immunized with attenuated SHIV89.6 is primarily mediated by CD8+ T cells that do not undergo dramatic systemic expansion after SIV challenge. These findings demonstrate that despite, and perhaps because of, minimal systemic expansion of T cells at the time of challenge, a stable population of effector-cytotoxic CD8+ T cells can provide significant protection from vaginal SIV challenge.

scholarly journals Expression of passively transferred immunity against an established tumor depends on generation of cytolytic T cells in recipient. Inhibition by suppressor T cells.

1983 ◽  
Vol 157 (5) ◽  
pp. 1448-1460 ◽  
Author(s):  
C D Mills ◽  
R J North
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Cell Response ◽  
Passive Transfer ◽  
T Cell Response ◽  
Suppressor T Cells ◽  
Tumor Bearing ◽  
Draining Lymph Node ◽  
Adoptive Immunity

The results of this study with the P815 mastocytoma confirm the results of previous studies that showed that the passive transfer of tumor-sensitized T cells from immunized donors can cause the regression of tumors growing in T cell-deficient (TXB) recipients, but not in normal recipients. The key additional finding was that the expression of adoptive immunity against tumors growing in TXB recipients is immediately preceded by a substantial production of cytolytic T cells in the recipients' draining lymph node. On the other hand, failure of adoptive immunity to be expressed against tumors growing in normal recipients was associated with a cytolytic T cell response of much lower magnitude, and a similar low magnitude response was generated in TXB recipients infused with normal spleen cells and in tumor-bearing control mice. Because the passively transferred sensitized T cells possessed no cytolytic activity of their own, the results indicate that the 6-8-d delay before adoptive immunity is expressed represents the time needed for passively transferred helper or memory T cells to give rise to a cytolytic T cell response of sufficient magnitude to destroy the recipient's tumor. In support of this interpretation was the additional finding that inhibition of the expression of adoptive immunity by the passive transfer of suppressor T cells from tumor-bearing donors was associated with a substantially reduced cytolytic T cell response in the recipient's draining lymph node. The results serve to illustrate that interpretation of the results of adoptive immunization experiments requires a knowledge of the events that take place in the adoptively immunized recipient. They support the interpretation that suppressor T cells function in this model to "down-regulate" the production of cytolytic effector T cells.

scholarly journals Diversity of the T-Cell Response to Pulmonary Cryptococcus neoformans Infection

2006 ◽  
Vol 74 (8) ◽  
pp. 4538-4548 ◽  
Author(s):  
Dennis M. Lindell ◽  
Megan N. Ballinger ◽  
Roderick A. McDonald ◽  
Galen B. Toews ◽  
Gary B. Huffnagle
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cryptococcus Neoformans ◽  
Cell Response ◽  
Primary Response ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Lymphoid Tissues ◽  
Cell Mediated Immunity ◽  
Antigen Specificity

ABSTRACT Cell-mediated immunity plays an important role in immunity to the pathogenic fungus Cryptococcus neoformans. However, the antigen specificity of the T-cell response to C. neoformans remains largely unknown. In this study, we used two approaches to determine the antigen specificity of the T-cell response to C. neoformans. We report here that a diverse T-cell receptor (TCR) Vβ repertoire was maintained throughout the primary response to pulmonary C. neoformans infection in immunocompetent mice. CD4+ T-cell deficiency resulted in relative expansion of all CD8+ T-cell subsets. During a secondary immune response, preferential usage of a TCR Vβ subset in CD4+ T cells occurred in single individuals, but the preferences were “private” and not shared between individuals. Both CD4+ and CD8+ T cells from the secondary lymphoid tissues of immunized mice proliferated in response to a variety of C. neoformans antigens, including heat-killed whole C. neoformans, culture filtrate antigen, C. neoformans lysate, and purified cryptococcal mannoprotein. CD4+ and CD8+ T cells from the secondary lymphoid tissues of mice undergoing a primary response to C. neoformans proliferated in response to C. neoformans lysate. In response to stimulation with C. neoformans lysate, lung CD4+ and CD8+ T cells produced the effector cytokines tumor necrosis factor alpha and gamma interferon. These results demonstrate that a diverse T-cell response is generated in response to pulmonary C. neoformans infection.

scholarly journals T cells Mediate Progression of Load-Induced Osteoarthritis

2020 ◽  
Author(s):  
Tibra A. Wheeler ◽  
Adrien Y. Antoinette ◽  
Matthew J. Kim ◽  
Marjolein C. H. van der Meulen ◽  
Ankur Singh
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Lymph Nodes ◽  
Mechanical Loading ◽  
Joint Damage ◽  
Γδ T Cells ◽  
Cartilage Degradation ◽  
T Cell Response ◽  
Lymphoid Tissues

AbstractOsteoarthritis (OA) is a degenerative disease that manifests as joint damage and synovial inflammation. To date, most studies have focused on the decrease in cartilage stiffness, chondrocyte viability, and changes in matrix-degrading enzymes. With the exception of a few inflammatory cytokines and macrophages, the immune response in OA is poorly characterized, and the crosstalk of joint damage with T and B cells in local lymph nodes is unknown. Here, using an in vivo mouse model of mechanical loading of mouse tibia, we demonstrate that CD8+ T cells and subsets of CD4+ T cells, and not B cells, increase in the local lymph nodes and contribute to the progression of load-induced OA pathology. We demonstrate that T cell response is sex- and age-dependent. Mechanical loading of T cell knock-out mice that lack αβ T cell receptor carrying cells resulted in attenuation of both cartilage degradation and osteophyte formation in loaded joints, with a concomitant increase in γδ+ T cells. Restricting the migration of T cells in lymphoid tissues through the systemic treatment using Sphingosine-1-phosphate (S1P) inhibitor, decreased localization of T cells in synovium, and attenuated cartilage degradation. Our results lay the foundation of the role T cells play in the joint damage of load-induced OA and allude to the use of S1P inhibitors and T cell immunotherapies for slowing the progression of OA pathology.

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 Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination

2015 ◽  
Vol 112 (10) ◽  
pp. 3050-3055 ◽  
Author(s):  
Rama S. Akondy ◽  
Philip L. F. Johnson ◽  
Helder I. Nakaya ◽  
Srilatha Edupuganti ◽  
Mark J. Mulligan ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Yellow Fever ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Virus Load

CD8 T cells are a potent tool for eliminating intracellular pathogens and tumor cells. Thus, eliciting robust CD8 T-cell immunity is the basis for many vaccines under development. However, the relationship between antigen load and the magnitude of the CD8 T-cell response is not well-described in a human immune response. Here we address this issue by quantifying viral load and the CD8 T-cell response in a cohort of 80 individuals immunized with the live attenuated yellow fever vaccine (YFV-17D) by sampling peripheral blood at days 0, 1, 2, 3, 5, 7, 9, 11, 14, 30, and 90. When the virus load was below a threshold (peak virus load < 225 genomes per mL, or integrated virus load < 400 genome days per mL), the magnitude of the CD8 T-cell response correlated strongly with the virus load (R2∼ 0.63). As the virus load increased above this threshold, the magnitude of the CD8 T-cell responses saturated. Recent advances in CD8 T-cell–based vaccines have focused on replication-incompetent or single-cycle vectors. However, these approaches deliver relatively limited amounts of antigen after immunization. Our results highlight the requirement that T-cell–based vaccines should deliver sufficient antigen during the initial period of the immune response to elicit a large number of CD8 T cells that may be needed for protection.

scholarly journals Single cell analysis of host response to helminth infection reveals the clonal breadth, heterogeneity, and tissue-specific programming of the responding CD4+ T cell repertoire

2021 ◽  
Vol 17 (6) ◽  
pp. e1009602
Author(s):  
Ivy K. Brown ◽  
Nathan Dyjack ◽  
Mindy M. Miller ◽  
Harsha Krovi ◽  
Cydney Rios ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Cell Response ◽  
Helminth Infection ◽  
T Cell Response ◽  
Specific Gene ◽  
Nippostrongylus Brasiliensis ◽  
Tissue Specific ◽  
Antigen Reactivity

The CD4+ T cell response is critical to host protection against helminth infection. How this response varies across different hosts and tissues remains an important gap in our understanding. Using IL-4-reporter mice to identify responding CD4+ T cells to Nippostrongylus brasiliensis infection, T cell receptor sequencing paired with novel clustering algorithms revealed a broadly reactive and clonally diverse CD4+ T cell response. While the most prevalent clones and clonotypes exhibited some tissue selectivity, most were observed to reside in both the lung and lung-draining lymph nodes. Antigen-reactivity of the broader repertoires was predicted to be shared across both tissues and individual mice. Transcriptome, trajectory, and chromatin accessibility analysis of lung and lymph-node repertoires revealed three unique but related populations of responding IL-4+ CD4+ T cells consistent with T follicular helper, T helper 2, and a transitional population sharing similarity with both populations. The shared antigen reactivity of lymph node and lung repertoires combined with the adoption of tissue-specific gene programs allows for the pairing of cellular and humoral responses critical to the orchestration of anti-helminth immunity.

Effect of Melan-Α/Μart-1-peptide vaccination plus IMP321 on antitumor immunity and clinical benefit in patients receiving autologous PBMCs after lymphodepletion.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20011-e20011
Author(s):  
Emanuela Romano ◽  
Helene Bichat ◽  
Athina Stravodimou ◽  
Pedro Romero ◽  
Speiser E Daniel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Clinical Benefit ◽  
Fold Increase ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Great Promise ◽  
Control Group ◽  
Significant Difference

e20011 Background: Immunotherapy offers great promise for cancer treatmet. Strong evidence supports adoptive cell transfer (ACT) and immunemodulation for regression of advanced melanoma. Few studies assessed the potential synergy between these two strategies. Methods: Twelve patients with metastatic melanoma received multiple Melan-A/Mart-1-peptide vaccinations with (n=6) or without (n=6) IMP321 (LAG-3Ig fusion protein) as an adjuvant in combination with lymphodepleting chemotherapy and ACT. All patients were selected on the basis of ex vivo detectable Melan-A-specific CD8 T cell responses and were immunized at day (D) 0, 8, 15, 22, 28, 52, and 74 post-reinfusion. Results: One-week after reinfusion of bulk autologous PBMCs, a significant expansion of Melan-A-specific CD8 T cells was measured in >83% (n=5) and <17% (n=1) of patients from the IMP321 and control groups, respectively (p=0.02). Compared to the control group, the mean fold increase of Melan-A-specific CD8 T cells was respectively >2-, >4-, and >6-fold higher in the IMP321 group at D15, D30, and D60 (p=0.02). A long-lasting Melan-A-specific CD8 T-cell response was significantly associated with IMP321 (p<0.001). A higher proportion of Melan-A-specific CD8 TEMRA (i.e., CD45RA+CCR7-CD127-) cells was observed in the IMP321 group at the peak of the response (p <0.002), whereas no significant difference was observed in the expression of co-inhibitory receptors (i.e., PD-1, 2B4, TIM3, CD160). IMP321 was associated with a significantly (p<0.04) reduced expansion of regulatory T cells (TREGS); we observed a negative correlation between the fold increase of Melan-A-specific CD8 T cells and the relative expansion of TREGS. Clinical benefit (assessed as CR, PR, and SD) was observed in none of the control patients vs 67% (4/6) of patients from the IMP321 group, (p=0.02). Conclusions: Vaccination with IMP321 as an adjuvant in combination with lymphodepleting chemotherapy and ACT provided clinical benefit and this was associated with a more robust and durable cellular antitumor immune response, supporting further development of IMP321 for future immunotherapeutic strategies. Clinical trial information: NCT00324623.

scholarly journals Anaplasma marginale Infection with Persistent High-Load Bacteremia Induces a Dysfunctional Memory CD4+ T Lymphocyte Response but Sustained High IgG Titers

2010 ◽  
Vol 17 (12) ◽  
pp. 1881-1890 ◽  
Author(s):  
Sushan Han ◽  
Junzo Norimine ◽  
Kelly A. Brayton ◽  
Guy H. Palmer ◽  
Glen A. Scoles ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Persistent Infection ◽  
Peripheral Blood ◽  
Cell Response ◽  
T Cell Responses ◽  
Anaplasma Marginale ◽  
High Load ◽  
T Cell Response ◽  
Cell Responses

ABSTRACT Control of blood-borne infections is dependent on antigen-specific effector and memory T cells and high-affinity IgG responses. In chronic infections characterized by a high antigen load, it has been shown that antigen-specific T and B cells are vulnerable to downregulation and apoptosis. Anaplasma marginale is a persistent infection of cattle characterized by acute and chronic high-load bacteremia. We previously showed that CD4+ T cells primed by immunization with an A. marginale outer membrane protein were rapidly deleted following infection. Furthermore, peripheral blood T cell responses to bacteria were not observed after acute infection was controlled, suggesting dysfunctional T cell priming to other A. marginale antigens. The current study more closely investigated the kinetics of A. marginale-specific CD4+ T cell responses primed during infection. Frequent sampling of peripheral blood and spleens revealed that antigen-specific CD4+ T cell responses were first detected at 5 to 7 weeks, but the responses were sporadic and transient thereafter. A similar pattern was observed in animals sampled weekly for nearly 1 year. Paradoxically, by 2 weeks of infection, cattle had developed high titers of A. marginale-specific IgG, which remained high throughout persistent infection. This dysfunctional CD4+ T cell response to infection is consistent with continual downregulation or deletion of newly primed effector T cells, similar to what was observed for immunization-induced T cells following A. marginale infection. The failure to establish a strong memory T cell response during A. marginale infection likely contributes to bacterial persistence.

scholarly journals Mimicry of the a determinant of hepatitis B surface antigen by an antiidiotypic antibody. I. Evaluation in hepatitis B surface antigen responder and nonresponder strains.

1993 ◽  
Vol 177 (1) ◽  
pp. 127-134 ◽  
Author(s):  
M W Pride ◽  
A Thakur ◽  
Y Thanavala
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Hepatitis B ◽  
Surface Antigen ◽  
Hepatitis B Surface Antigen ◽  
T Cell Response

B and T cell responses of several strains of mice, immunized with a monoclonal antiidiotype (anti-Id) that mimics the a determinant of hepatitis B surface antigen (HBsAg), were studied to determine if the immune response to the anti-Id was regulated by H-2-linked immune response genes as has been previously observed for HBsAg. We report that immunization with anti-Id could elicit HBsAg-specific antibodies in mice of the H-2d,q, or f haplotype and in an outbred wild mouse strain (Mus spretus), thus circumventing the H-2 haplotype restriction pattern observed when immunizing with HBsAg in H-2f mice. Purified lymph node T cells from mice of the H-2d or q haplotype and M. spretus that were primed in vivo with HBsAg or anti-Id could be stimulated in vitro with either HBsAg or anti-Id but not with an irrelevant antibody of the same subclass as the anti-Id. However, purified lymph node T cells from H-2f mice that were primed in vivo with the anti-Id could only be stimulated in vitro with anti-Id. No in vitro stimulation whatsoever was observed in H-2f mice immunized with HBsAg. The effect of processing and presentation of the anti-Id by antigen-presenting cells (APC) was studied in mice of the H-2d haplotype. Stimulation of purified lymph node T cells by HBsAg and anti-Id was shown to be strictly dependent on APC and restricted by major histocompatibility complex class II antigens at the I-A locus. Treatment of APC with paraformaldehyde or chloroquine abrogated the T cell response to all antigens except for a nine-amino acid synthetic peptide representing a partial analogue of the group a determinant of HBsAg S(139-147). The significance of these results is discussed in the context of understanding the mechanism of mimicry elicited by the anti-Id.

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