scholarly journals CD4+ and CD8+ T cells producing Th1 and Th17 cytokines are involved in the pathogenesis of autoimmune orchitis

Reproduction ◽  
2011 ◽  
Vol 141 (2) ◽  
pp. 249-258 ◽  
Author(s):  
Patricia Jacobo ◽  
Cecilia Valeria Pérez ◽  
María Susana Theas ◽  
Vanesa Anabella Guazzone ◽  
Livia Lustig
Keyword(s):  
T Cells ◽  
Western Blot ◽  
Cd8 T Cells ◽  
Chronic Phase ◽  
Interferon Γ ◽  
Seminiferous Tubules ◽  
Interleukin 17 ◽  
Effector Cells ◽  
Th17 Cytokines ◽  
Autoimmune Orchitis

Experimental autoimmune orchitis (EAO) is a useful model to study chronic testicular inflammation and infertility. EAO is characterized by severe damage of seminiferous tubules with germ cells that undergo apoptosis and sloughing. We previously reported an increase in CD4+ and CD8+ effector T cells in the testes of rats with EAO. Since cytokine patterns determine T cell effector functions, in the present work we analyzed the cytokines expressed by these cells during disease development. By flow cytometry, we detected an increase in the number of tumor necrosis factor-α (TNF) and interferon -γ (IFNG)-producing CD4+ T cells in the testis at EAO onset. As the severity of the disease progressed, these cells declined while CD8+ T cells producing TNF and IFNG increased, with the predominance of IFNG expression. As a novel finding, we identified by immunofluorescence CD4+ interleukin 17 (IL17)+ and CD8+ IL17+ cells in the testes of EAO rats, with CD4+ and CD8+ T cells predominating at the onset and in the chronic phase of EAO respectively. Moreover, IL17 (western blot) and IL23 content (ELISA) increased in EAO, with maximum levels in the chronic phase. These results suggest the involvement of CD4+ T helper (Th) 1 and Th17 subsets as co-effector cells governing EAO onset, as well as the central contribution of CD8+ T cells producing Th1 and Th17 cytokines in the maintenance of chronic inflammation. The expression of T-bet and RORγt (western blot) in the testis over the course of disease also supports the presence of Th1 and Th17 cells in the testes of EAO rats.

scholarly journals Type 17 CD8+ T cells display enhanced antitumor immunity

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 596-599 ◽  
Author(s):  
Christian S. Hinrichs ◽  
Andrew Kaiser ◽  
Chrystal M. Paulos ◽  
Lydie Cassard ◽  
Luis Sanchez-Perez ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Therapy ◽  
Cd8 T Cells ◽  
Antitumor Immunity ◽  
Killer Cell ◽  
Cd8 T Cell ◽  
Interferon Γ ◽  
Interleukin 17 ◽  
Effector Cells

Abstract Interleukin-17 (IL-17)–secreting CD8+ T cells have been described, but they have not been thoroughly studied and they do not have a known role in cancer immunotherapy. We skewed CD8+ T cells to secrete IL-17 through priming in Th17-polarizing conditions. IL-17–producing CD8+ T cells demonstrated reduced expression of Eomes and diminished cytolytic differentiation in vitro. However, after adoptive transfer, these cells converted to interferon-γ–producing effector cells and mediated regression of large, established tumors. This improved antitumor immunity was associated with increased expression of IL-7R-alpha, decreased expression of killer cell lectin-like receptor G1, and enhanced persistence of the transferred cells. This report is the first description of a cancer therapy with IL-17–secreting CD8+ T cells. These findings have implications for the improvement of CD8+ T cell–based adoptive immunotherapy.

scholarly journals Acquisition of Selectin Binding and Peripheral Homing Properties by CD4+ and CD8+ T Cells

1999 ◽  
Vol 189 (11) ◽  
pp. 1765-1776 ◽  
Author(s):  
Huijuan Xie ◽  
Yaw-Chyn Lim ◽  
Francis W. Luscinskas ◽  
Andrew H. Lichtman
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Chemokine Receptors ◽  
Interferon Γ ◽  
T Cell Subsets ◽  
Effector Cells ◽  
Inflammatory Site ◽  
Selectin Ligand ◽  
Inducible Protein ◽  
Selectin Binding

Different T cell subsets exhibit distinct capacities to migrate into peripheral sites of inflammation, and this may in part reflect differential expression of homing receptors and chemokine receptors. Using an adoptive transfer approach, we examined the ability of functionally distinct subsets of T cells to home to a peripheral inflammatory site. The data directly demonstrate the inability of naive T cells and the ability of effector cells to home to inflamed peritoneum. Furthermore, interleukin (IL)-12 directs the differentiation of either CD4+ or CD8+ T cells into effector populations that expresses functional E- and P-selectin ligand and that are preferentially recruited into the inflamed peritoneum compared with T cells differentiated in the presence of IL-4. Recruitment can be blocked by anti–E- and –P-selectin antibodies. The presence of antigen in the peritoneum promotes local proliferation of recruited T cells, and significantly amplifies the Th1 polarization of the lymphocytic infiltrate. Preferential recruitment of Th1 cells into the peritoneum is also seen when cytokine response gene 2 (CRG-2)/interferon γ–inducible protein 10 (IP-10) is used as the sole inflammatory stimulus. We have also found that P-selectin binds only to antigen-specific T cells in draining lymph nodes after immunization, implying that both antigen- and cytokine-mediated signals are required for expression of functional selectin-ligand.

scholarly journals S100A4+ macrophages facilitate zika virus invasion and persistence in the seminiferous tubules via interferon-gamma mediation

2020 ◽  
Vol 16 (12) ◽  
pp. e1009019
Author(s):  
Wei Yang ◽  
Yan-Hua Wu ◽  
Shuang-Qing Liu ◽  
Zi-Yang Sheng ◽  
Zi-Da Zhen ◽  
...  
Keyword(s):  
T Cells ◽  
Interferon Gamma ◽  
Cellular Immunity ◽  
Cd8 T Cells ◽  
Zika Virus ◽  
Interferon Γ ◽  
Seminiferous Tubules ◽  
Spermatogenic Cells ◽  
Zikv Infection ◽  
M1 Macrophages

Testicular invasion and persistence are features of Zika virus (ZIKV), but their mechanisms are still unknown. Here, we showed that S100A4+ macrophages, a myeloid macrophage subpopulation with susceptibility to ZIKV infection, facilitated ZIKV invasion and persistence in the seminiferous tubules. In ZIKV-infected mice, S100A4+ macrophages were specifically recruited into the interstitial space of testes and differentiated into interferon-γ-expressing M1 macrophages. With interferon-γ mediation, S100A4+ macrophages down-regulated Claudin-1 expression and induced its redistribution from the cytosol to nucleus, thus increasing the permeability of the blood-testis barrier which facilitated S100A4+ macrophages invasion into the seminiferous tubules. Intraluminal S100A4+ macrophages were segregated from CD8+ T cells and consequently helped ZIKV evade cellular immunity. As a result, ZIKV continued to replicate in intraluminal S100A4+ macrophages even when the spermatogenic cells disappeared. Deficiencies in S100A4 or interferon-γ signaling both reduced ZIKV infection in the seminiferous tubules. These results demonstrated crucial roles of S100A4+ macrophages in ZIKV infection in testes.

scholarly journals Differential Antigen Specificity of Hepatitis C Virus–Specific Interleukin 17– and Interferon γ–Producing CD8+ T Cells During Chronic Infection

2012 ◽  
Vol 205 (7) ◽  
pp. 1142-1146 ◽  
Author(s):  
Stefanie Grafmueller ◽  
Eva Billerbeck ◽  
Hubert E. Blum ◽  
Christoph Neumann-Haefelin ◽  
Robert Thimme
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cd8 T Cells ◽  
Chronic Infection ◽  
Interferon Γ ◽  
Interleukin 17 ◽  
Antigen Specificity

Rapid allergen-induced interleukin-17 and interferon-γ secretion by skin-resident memory CD8+T cells

2016 ◽  
Vol 76 (4) ◽  
pp. 218-227 ◽  
Author(s):  
Jonas D. Schmidt ◽  
Malin G. Ahlström ◽  
Jeanne D. Johansen ◽  
Beatrice Dyring-Andersen ◽  
Christina Agerbeck ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Interferon Γ ◽  
Interleukin 17 ◽  
Memory Cd8 T Cells

scholarly journals Phenotypic and Functional Analysis of Cd8+ T Cells Undergoing Peripheral Deletion in Response to Cross-Presentation of Self-Antigen

2001 ◽  
Vol 194 (6) ◽  
pp. 707-718 ◽  
Author(s):  
Javier Hernandez ◽  
Sandra Aung ◽  
William L. Redmond ◽  
Linda A. Sherman
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Interferon Γ ◽  
Cytolytic Activity ◽  
Presentation Of Self ◽  
Effector Cells ◽  
Cross Presentation ◽  
Influenza Hemagglutinin ◽  
Antigen Presenting ◽  
Self Antigen

Not all T cells specific for autoantigens are eliminated in the thymus, and therefore alternate mechanisms are required to prevent potentially autoreactive T cells from developing into effectors. Adoptive transfer of CD8+ T cells from influenza hemagglutinin-specific Clone 4 TCR transgenic mice into mice that express hemagluttinin in the pancreatic islets results in tolerance. This is preceded by activation of Clone 4 T cells that encounter antigen cross-presented in the draining lymph nodes of the pancreas. In this report we compare the phenotype, function, and costimulatory requirements of Clone 4 T cells activated by endogenous self-antigen, with Clone 4 T cells stimulated by influenza virus. The cells undergoing tolerance upregulate both CD69 and CD44, yet only partially downregulate CD62L, and do not express CD49d or CD25. Most importantly, they lack the ability to produce interferon-γ in response to antigen and show no cytolytic activity. Clone 4 T cells disappear after several cycles of division, apparently without leaving the site of initial activation. Surprisingly, despite the fact that such stimulation occurs through recognition of antigen that is cross-presented by a professional antigen-presenting cell, we find this activation is not dependent on costimulation through CD28. These data demonstrate that the recognition by naive CD8+ T cells of cross-presented self-antigen results in localized proliferation and deletion, without the production of effector cells.

scholarly journals IL-15 induces antigen-independent expansion and differentiation of human naive CD8+ T cells in vitro

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2541-2546 ◽  
Author(s):  
Nuno L. Alves ◽  
Berend Hooibrink ◽  
Fernando A. Arosa ◽  
René A. W. van Lier
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Interferon Γ ◽  
T Cell Subsets ◽  
Memory Cd8 T Cells ◽  
Effector Cells ◽  
Independent Expansion

Abstract Recent studies in mice have shown that although interleukin 15 (IL-15) plays an important role in regulating homeostasis of memory CD8+ T cells, it has no apparent function in controlling homeostatic proliferation of naive T cells. We here assessed the influence of IL-15 on antigen-independent expansion and differentiation of human CD8+ T cells. Both naive and primed human T cells divided in response to IL-15. In this process, naive CD8+ T cells successively down-regulated CD45RA and CD28 but maintained CD27 expression. Concomitant with these phenotypic changes, naive cells acquired the ability to produce interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α), expressed perforin and granzyme B, and acquired cytotoxic properties. Primed CD8+ T cells, from both noncytotoxic (CD45RA-CD27+) and cytotoxic (CD45RA+CD27-) subsets, responded to IL-15 and yielded ample numbers of cytokine-secreting and cytotoxic effector cells. In summary, all human CD8+ T-cell subsets had the ability to respond to IL-15, which suggests a generic influence of this cytokine on CD8+ T-cell homeostasis in man. (Blood. 2003;102:2541-2546)

Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3065-3072 ◽  
Author(s):  
Michael R. Verneris ◽  
Mobin Karami ◽  
Jeanette Baker ◽  
Anishka Jayaswal ◽  
Robert S. Negrin
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Malignant Cell ◽  
Leukemic Cells ◽  
Target Cells ◽  
High Dose ◽  
Effector Cells ◽  
Nkg2d Expression

Abstract Activating and expanding T cells using T-cell receptor (TCR) cross-linking antibodies and interleukin 2 (IL-2) results in potent cytotoxic effector cells capable of recognizing a broad range of malignant cell targets, including autologous leukemic cells. The mechanism of target cell recognition has previously been unknown. Recent studies show that ligation of NKG2D on natural killer (NK) cells directly induces cytotoxicity, whereas on T cells it costimulates TCR signaling. Here we demonstrate that NKG2D expression is up-regulated upon activation and expansion of human CD8+ T cells. Antibody blocking, redirected cytolysis, and small interfering RNA (siRNA) studies using purified CD8+ T cells demonstrate that cytotoxicity against malignant target cells occurs through NKG2D-mediated recognition and signaling and not through the TCR. Activated and expanded CD8+ T cells develop cytotoxicity after 10 to 14 days of culture, coincident with the expression of the adapter protein DAP10. T cells activated and expanded in low (30 U/mL) and high (300 U/mL) concentrations of IL-2 both up-regulated NKG2D expression equally, but only cells cultured in high-dose IL-2 expressed DAP10 and were cytotoxic. Collectively these results establish that NKG2D triggering accounts for the majority of major histocompatibility complex (MHC)–unrestricted cytotoxicity of activated and expanded CD8+ T cells, likely through DAP10-mediated signaling. (Blood. 2004;103: 3065-3072)

Soluble CD70: a novel immunotherapeutic agent for experimental glioblastoma

2010 ◽  
Vol 113 (2) ◽  
pp. 280-285 ◽  
Author(s):  
James Miller ◽  
Guenter Eisele ◽  
Ghazaleh Tabatabai ◽  
Steffen Aulwurm ◽  
Gabriele von Kürthy ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Malignant Gliomas ◽  
Ectopic Expression ◽  
Glioma Cells ◽  
Interferon Γ ◽  
Soluble Form ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells

Object Given the overall poor outcome with current treatment strategies in malignant gliomas, immunotherapy has been considered a promising experimental approach to glioblastoma for more than 2 decades. A cell surface molecule, CD70, may induce potent antitumor immune responses via activation of the costimulatory receptor CD27 expressed on immune effector cells. There is evidence that a soluble form of CD70 (sCD70) may exhibit biological activity, too. A soluble costimulatory ligand is attractive because it may facilitate immune activation and may achieve a superior tissue distribution. Methods To test the antiglioma effect of sCD70, the authors genetically modified SMA-560 mouse glioma cells to secrete the extracellular domain of CD70. They assessed the immunogenicity of the transfected cells in cocultures with immune effector cells by the determination of immune cell proliferation and the release of interferon-γ. Syngeneic VM/Dk mice were implanted orthotopically with control or sCD70-releasing glioma cells to determine a survival benefit mediated by sCD70. Depletion studies were performed to identify the cellular mediators of prolonged survival of sCD70-releasing glioma-bearing mice. Results The authors found that ectopic expression of sCD70 enhanced the proliferation and interferon-γ release of syngeneic splenocytes in vitro. More importantly, sCD70 prolonged the survival of syngeneic VM/Dk mice bearing intracranial SMA-560 gliomas. The survival rate at 60 days increased from 5 to 45%. Antibody-mediated depletion of CD8-positive T cells abrogates the survival advantage conferred by sCD70. Conclusions These data suggest that sCD70 is a potent stimulator of antiglioma immune responses that depend critically on CD8-positive T cells. Soluble CD70 could be a powerful adjuvant for future immunotherapy trials for glioblastoma.

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