NIK signaling in dendritic cells but not in T cells is required for the development of effector T cells and cell-mediated immune responses

The canonical NF-κB pathway is a driving force for virtually all aspects of inflammation. Conversely, the role of the noncanonical NF-κB pathway and its central mediator NF-κB–inducing kinase (NIK) remains poorly defined. NIK has been proposed to be involved in the formation of TH17 cells, and its absence in TH cells renders them incapable of inducing autoimmune responses, suggesting a T cell–intrinsic role for NIK. Upon systematic analysis of NIK function in cell-mediated immunity, we found that NIK signaling is dispensable within CD4+ T cells but played a pivotal role in dendritic cells (DCs). We discovered that NIK signaling is required in DCs to deliver co-stimulatory signals to CD4+ T cells and that DC-restricted expression of NIK is sufficient to restore TH1 and TH17 responses as well as cell-mediated immunity in NIK−/− mice. When CD4+ T cells developed in the absence of NIK-sufficient DCs, they were rendered anergic. Reintroduction of NIK into DCs allowed developing NIK−/− CD4+ T cells to become functional effector populations and restored the development of autoimmune disease. Therefore, our data suggest that a population of thymic DCs requires NIK to shape the formation of most αβ CD4+ T effector lineages during early development.

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Role of dendritic cells infected with human herpesvirus 6 in virus transmission to CD4+ T cells

Virology ◽

10.1016/j.virol.2008.11.049 ◽

2009 ◽

Vol 385 (2) ◽

pp. 294-302 ◽

Cited By ~ 11

Author(s):

Masaya Takemoto ◽

Takayoshi Imasawa ◽

Koichi Yamanishi ◽

Yasuko Mori

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Virus Transmission ◽

Human Herpesvirus ◽

Human Herpesvirus 6 ◽

Herpesvirus 6

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Expanded circulating follicular dendritic cells facilitate immune responses in chronic HBV infection

10.21203/rs.3.rs-52170/v3 ◽

2020 ◽

Author(s):

Xiaoyi Li ◽

Qifan Zhang ◽

Wanyue Zhang ◽

Guofu Ye ◽

Yanchen Ma ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

B Cells ◽

Hepatitis B ◽

Immune Responses ◽

Cd4 T Cells ◽

Hbv Infection ◽

Follicular Dendritic Cells ◽

Chronic Hbv Infection ◽

Chronic Hbv

Abstract Background: The restoration of host hepatitis B virus (HBV)-specific antiviral immunity is an effective strategy for hepatitis B recovery. Follicular dendritic cells (FDCs) play a crucial role in immune regulation. The goal of the present study was to investigate the characteristics and functions of FDCs in chronic HBV infection. Methods: The frequencies of FDCs in peripheral blood, liver, and spleen were measured in patients with chronic HBV infection. Isolated FDCs from splenic tissues of HBV-related liver cirrhosis-induced hypersplenism patients were cultured with autologous intrasplenic CD4 + T cells and CD19 + B cells.Results: We found that patients with chronic HBV infection had a significantly increased frequency of circulating FDCs compared with that of healthy controls. Additionally, the frequency of circulating FDCs was positively correlated with that of intrahepatic and intrasplenic counterparts. Moreover, a positive correlation between the frequency of circulating FDCs and plasmablast and memory B cells, as well as C-X-C motif chemokine receptor type 5 (CXCR5) + CD4 + T cells and CXCR5 + CD8 + T cells was also observed. Notably, in vitro experiments demonstrated that FDCs derived from splenic tissues of chronic HBV patients facilitated interferon-γ and interleukin-21 production from autologous intrasplenic CD4 + T cells and promoted the proliferation of autologous intrasplenic CD19 + B cells. Conclusions: Expanded FDCs in patients with chronic HBV infection may favor the host immune responses against HBV. The identification of this unique population may contribute to a better understanding of the immune regulatory mechanisms and provide a potential immunotherapeutic target in chronic HBV infection.

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Prognostic Significance of Immunohistochemical Phenotypes in Patients Treated for High-Grade Cervical Intraepithelial Neoplasia

BioMed Research International ◽

10.1155/2013/831907 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 9

Author(s):

Massimo Origoni ◽

Marta Parma ◽

Giacomo Dell'Antonio ◽

Chiara Gelardi ◽

Chiara Stefani ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cervical Intraepithelial Neoplasia ◽

Clinical Outcomes ◽

Cd4 T Cells ◽

Prognostic Significance ◽

Intraepithelial Neoplasia ◽

Cell Mediated Immunity ◽

High Grade ◽

Recurrence Rates

Strong evidence exists that the host’s immune system plays a crucial role for the development of human papillomavirus-related cervical premalignant and malignant lesions. In particular, effective cell-mediated immunity (CMI) promotes spontaneous infection clearance and cancer precursors regression in healthy subjects, while immunosuppressed individuals are more likely to experience infection persistence, cervical intraepithelial neoplasia (CIN) lesions, and cervical cancer. In this study, the prognostic significance of immunohistochemical profiling of CD4+ T-cells, CD8+ T-cells, dendritic cells (CD11c+), T-bet+, and GATA-3+ transcription factors has been studied in surgical specimens of 34 consecutive women affected by high-grade cervical intraepithelial neoplasia (CIN2-3) submitted to cervical conization. Results have been correlated with the clinical outcomes at 24 months after treatment and statistically analyzed. Higher rates of CD4+ T-cells, CD11c+ dendritic cells, and T-bet+ transcription factor positivity showed a strong statistically significative correlation with favourable clinical outcomes (P≤0.0001). These data reinforce the evidence of the relevance of the host’s immune status in the natural history of HPV-related cervical disease and add a prognostic significance of the cervical immunological profile in terms of predicting significant lower recurrence rates.

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CD4+ T Cells Elicit Host Immune Responses to MHC Class II− Ovarian Cancer through CCL5 Secretion and CD40-Mediated Licensing of Dendritic Cells

The Journal of Immunology ◽

10.4049/jimmunol.0903247 ◽

2010 ◽

Vol 184 (10) ◽

pp. 5654-5662 ◽

Cited By ~ 52

Author(s):

Yolanda C. Nesbeth ◽

Diana G. Martinez ◽

Seiko Toraya ◽

Uciane K. Scarlett ◽

Juan R. Cubillos-Ruiz ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

Dendritic Cells ◽

Immune Responses ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Class Ii ◽

Host Immune Responses

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Monoclonal antibodies to LFA-1 and to CD4 inhibit the mixed leukocyte reaction after the antigen-dependent clustering of dendritic cells and T lymphocytes.

Journal of Experimental Medicine ◽

10.1084/jem.165.5.1403 ◽

1987 ◽

Vol 165 (5) ◽

pp. 1403-1417 ◽

Cited By ~ 94

Author(s):

K Inaba ◽

R M Steinman

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cell Mediated Immunity ◽

Lymphocyte Function ◽

Mixed Leukocyte Reaction ◽

Binding Assays ◽

Lymphocyte Blastogenesis ◽

And Function

T cell proliferation in response to many stimuli is known to occur in discrete clusters of dendritic cells (DC) and CD4+ helper lymphocytes. The role of lymphocyte function-associated antigen (LFA-1) and CD4 in the formation and function of these clusters has been evaluated in the mixed leukocyte reaction (MLR). By day 1 of the control MLR, most of the DC and responsive T cells are associated in discrete aggregates. Addition of anti-LFA-1 and CD4 reagents does not block DC-T aggregation but reduces the subsequent proliferative response by 80-90%. Anti-LFA-1 disassembles newly formed DC-T cell aggregates, whereas anti-CD4 inhibits blastogenesis without disrupting the cluster. Binding of DC to sensitized, antigen-specific CD4+ cells has been studied using lymphoblasts isolated at day 4 of the MLR. It has been shown previously that greater than 80% blasts rebind to DC in an antigen-specific fashion in rapid (10 min) binding assays. Antigen-dependent DC-T binding is blocked by anti-Ia but not by mAb to LFA-1 or CD4. However, the bound anti-CD4-coated lymphocytes are unable to release IL-2. Anti-LFA-1-coated T cells release IL-2 but are easily disaggregated after binding to DC. These findings lead to two conclusions. LFA-1 and CD4 are not involved in the initial steps whereby DC bind to T cells but exert an independent and subsequent role. LFA-1 acts to stabilize the DC-T cluster, while CD4 contributes to lymphocyte blastogenesis and IL-2 release. Because DC but not other presenting cells cluster unprimed lymphocytes, it seems likely that an antigen-independent mechanism distinct from LFA-1 and CD4 mediates aggregate formation at the onset of cell-mediated immunity.

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DC-SIGN–mediated Infectious Synapse Formation Enhances X4 HIV-1 Transmission from Dendritic Cells to T Cells

Journal of Experimental Medicine ◽

10.1084/jem.20041356 ◽

2004 ◽

Vol 200 (10) ◽

pp. 1279-1288 ◽

Cited By ~ 182

Author(s):

Jean-François Arrighi ◽

Marjorie Pion ◽

Eduardo Garcia ◽

Jean-Michel Escola ◽

Yvette van Kooyk ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Hiv Infection ◽

Cd4 T Cells ◽

Synapse Formation ◽

Model Systems ◽

Hiv 1 ◽

Infectious Synapse

Dendritic cells (DCs) are essential for the early events of human immunodeficiency virus (HIV) infection. Model systems of HIV sexual transmission have shown that DCs expressing the DC-specific C-type lectin DC-SIGN capture and internalize HIV at mucosal surfaces and efficiently transfer HIV to CD4+ T cells in lymph nodes, where viral replication occurs. Upon DC–T cell clustering, internalized HIV accumulates on the DC side at the contact zone (infectious synapse), between DCs and T cells, whereas HIV receptors and coreceptors are enriched on the T cell side. Viral concentration at the infectious synapse may explain, at least in part, why DC transmission of HIV to T cells is so efficient. Here, we have investigated the role of DC-SIGN on primary DCs in X4 HIV-1 capture and transmission using small interfering RNA–expressing lentiviral vectors to specifically knockdown DC-SIGN. We demonstrate that DC-SIGN− DCs internalize X4 HIV-1 as well as DC-SIGN+ DCs, although binding of virions is reduced. Strikingly, DC-SIGN knockdown in DCs selectively impairs infectious synapse formation between DCs and resting CD4+ T cells, but does not prevent the formation of DC–T cells conjugates. Our results demonstrate that DC-SIGN is required downstream from viral capture for the formation of the infectious synapse between DCs and T cells. These findings provide a novel explanation for the role of DC-SIGN in the transfer and enhancement of HIV infection from DCs to T cells, a crucial step for HIV transmission and pathogenesis.

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Delineating the role of CD4+ T cells in the activation of human cytomegalovirus-specific immune responses following immunization with Ad-gBCMVpoly vaccine: implications for vaccination of immunocompromised individuals

Journal of General Virology ◽

10.1099/vir.0.025742-0 ◽

2010 ◽

Vol 91 (12) ◽

pp. 2994-3001 ◽

Cited By ~ 7

Author(s):

J. Zhong ◽

R. Khanna

Keyword(s):

T Cells ◽

Immune Responses ◽

Human Cytomegalovirus ◽

Cd4 T Cells

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Cellular immune responses and changes in VL after a Dendritic Cells (DC)-based therapeutic vaccine in cART treated chronic HIV-infected patients with CD4 T cells above 450/mm

Retrovirology ◽

10.1186/1742-4690-9-s2-o42 ◽

2012 ◽

Vol 9 (Suppl 2) ◽

pp. O42

Author(s):

F García ◽

AC Guardo ◽

M Maleno ◽

L Papagno ◽

M Bargalló ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune Responses ◽

Cd4 T Cells ◽

Therapeutic Vaccine ◽

Cellular Immune Responses ◽

Cellular Immune

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Independent Prognostic Potential of GNPNAT1 in Lung Adenocarcinoma

BioMed Research International ◽

10.1155/2020/8851437 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Xiangyu Zheng ◽

Yongwei Li ◽

Chao Ma ◽

Jinjun Zhang ◽

Yanmin Zhang ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

B Cells ◽

Lung Adenocarcinoma ◽

Cd4 T Cells ◽

Prognostic Value ◽

Marker Genes ◽

Immune Signatures ◽

Cox Analysis

Background. Glucosamine-Phosphate N-Acetyltransferase 1 (GNPNAT1) is a critical enzyme in the biosynthesis of uridine diphosphate-N-acetylglucosamine. It has many important functions, such as protein binding, monosaccharide binding, and embryonic development and growth. However, the role of GNPNAT1 in lung adenocarcinoma (LUAD) remains unclear. Methods. In this study, we explored the expression pattern and prognostic value of GNPNAT1 in LUAD across TCGA and GEO databases and assessed its independent prognostic value via Cox analysis. LinkedOmics and GEPIA2 were applied to investigate coexpression and functional networks associated with GNPNAT1. The TIMER web tool was deployed to assess the correlation between GNPNAT1 and the main six types of tumor-infiltrating immune cells. Besides, the correlations between GNPNAT1 and the LUAD common genetic mutations, TMB, and immune signatures were examined. Results. GNPNAT1 was validated upregulated in tumor tissues in TCGA-LUAD and GEO cohorts. Moreover, in both TCGA and GEO cohorts, high GNPNAT1 expression was found to be associated with poor overall survival. Cox analysis showed that high GNPNAT1 expression was an independent risk factor for LUAD. Functional network analysis suggested that GNPNAT1 regulates cell cycle, ribosome, proteasome, RNA transport, and spliceosome signaling through pathways involving multiple cancer-related kinases and E2F family. In addition, GNPNAT1 correlated with infiltrating levels of B cells, CD4+ T cells, and dendritic cells. B cells and dendritic cells could predict the outcome of LUAD, and B cells and CD4+ T cells were significant independent risk factors. The TMB and mutations of KRAS, EGFR, STK11, and TP53 were correlated with GNPNAT1. At last, the correlation analysis showed GNPNAT1 correlated with most of the immune signatures we performed. Conclusion. Our findings showed that GNPNAT1 was correlated to the prognosis and immune infiltration of LUAD. In particular, the tight relationship between GNPNAT1 and B cell marker genes may be the epicenter of the immune response and one of the key factors affecting the prognosis. Our findings laid the foundation for further research on the immunomodulatory role of GNPNAT1 in LUAD.

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