CD8+ T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules: a critical role for P-selectin glycoprotein ligand-1

The CD4 protein plays a critical role in the development and function of the immune system. To gain more insight into the mechanism of expression of the human CD4 gene, we cloned 42.2 kbp of genomic sequences comprising the CD4 gene and its surrounding sequences. Studies with transgenic mice revealed that a 12.6-kbp fragment of the human CD4 gene (comprising 2.6 kbp of 5' sequences upstream of the transcription initiation site, the first two exons and introns, and part of exon 3) contains the sequences required to support the appropriate expression in murine mature CD4+ CD8- T cells and macrophages but not in immature double-positive CD4+ CD8+ T cells. Expression in CD4+ CD8+ T cells was found to require additional regulatory elements present in a T-cell enhancer fragment recently identified for the murine CD4 gene (S. Sawada and D. R. Littman, Mol. Cell. Biol. 11:5506-5515, 1991). These results suggest that expression of CD4 in mature and immature T-cell subsets may be controlled by distinct and independent regulatory elements. Alternatively, specific regulatory elements may control the expression of CD4 at different levels in mature and immature T-cell subsets. Our data also indicate that mouse macrophages contain the regulatory factors necessary to transcribe the human CD4 gene.

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DC-Based Vaccines for Cancer Immunotherapy

Vaccines ◽

10.3390/vaccines8040706 ◽

2020 ◽

Vol 8 (4) ◽

pp. 706

Author(s):

Chunmei Fu ◽

Li Zhou ◽

Qing-Sheng Mi ◽

Aimin Jiang

Keyword(s):

Clinical Trials ◽

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd8 T Cells ◽

Critical Role ◽

Cd8 T Cell ◽

T Cell Immunity ◽

Cell Responses ◽

Cell Immunity

As the sentinels of the immune system, dendritic cells (DCs) play a critical role in initiating and regulating antigen-specific immune responses. Cross-priming, a process that DCs activate CD8 T cells by cross-presenting exogenous antigens onto their MHCI (Major Histocompatibility Complex class I), plays a critical role in mediating CD8 T cell immunity as well as tolerance. Current DC vaccines have remained largely unsuccessful despite their ability to potentiate both effector and memory CD8 T cell responses. There are two major hurdles for the success of DC-based vaccines: tumor-mediated immunosuppression and the functional limitation of the commonly used monocyte-derived dendritic cells (MoDCs). Due to their resistance to tumor-mediated suppression as inert vesicles, DC-derived exosomes (DCexos) have garnered much interest as cell-free therapeutic agents. However, current DCexo clinical trials have shown limited clinical benefits and failed to generate antigen-specific T cell responses. Another exciting development is the use of naturally circulating DCs instead of in vitro cultured DCs, as clinical trials with both human blood cDC2s (type 2 conventional DCs) and plasmacytoid DCs (pDCs) have shown promising results. pDC vaccines were particularly encouraging, especially in light of promising data from a recent clinical trial using a human pDC cell line, despite pDCs being considered tolerogenic and playing a suppressive role in tumors. However, how pDCs generate anti-tumor CD8 T cell immunity remains poorly understood, thus hindering their clinical advance. Using a pDC-targeted vaccine model, we have recently reported that while pDC-targeted vaccines led to strong cross-priming and durable CD8 T cell immunity, cross-presenting pDCs required cDCs to achieve cross-priming in vivo by transferring antigens to cDCs. Antigen transfer from pDCs to bystander cDCs was mediated by pDC-derived exosomes (pDCexos), which similarly required cDCs for cross-priming of antigen-specific CD8 T cells. pDCexos thus represent a new addition in our arsenal of DC-based cancer vaccines that would potentially combine the advantage of pDCs and DCexos.

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CD8+ T-Cells as Immune Regulators of Multiple Sclerosis

Frontiers in Immunology ◽

10.3389/fimmu.2015.00619 ◽

2015 ◽

Vol 6 ◽

Cited By ~ 39

Author(s):

Sushmita Sinha ◽

Alexander W. Boyden ◽

Farah R. Itani ◽

Michael P. Crawford ◽

Nitin J. Karandikar

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Cd8 T Cells

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Multiple sclerosis: Brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0308689100 ◽

2004 ◽

Vol 101 (8) ◽

pp. 2428-2433 ◽

Cited By ~ 233

Author(s):

C. Skulina ◽

S. Schmidt ◽

K. Dornmair ◽

H. Babbe ◽

A. Roers ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Cerebrospinal Fluid ◽

Cd8 T Cells

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NKG2D Polymorphism in Melanoma Patients from Southeastern Spain

Cancers ◽

10.3390/cancers11040438 ◽

2019 ◽

Vol 11 (4) ◽

pp. 438 ◽

Cited By ~ 1

Author(s):

Lourdes Gimeno ◽

Helios Martínez-Banaclocha ◽

M. Bernardo ◽

José Bolarin ◽

Luis Marín ◽

...

Keyword(s):

T Cells ◽

Natural Killer ◽

Cd8 T Cells ◽

Nk Cell ◽

Critical Role ◽

Healthy Controls ◽

Nucleotide Polymorphisms ◽

Southeastern Spain ◽

Melanoma Patients ◽

Risk Of Cancer

Background: Natural killer (NK) and CD8+ T cells are involved in the immune response against melanoma. C-Type lectin-like NK cell receptors are located in the Natural Killer Complex (NKC) region 12p13.2-p12.3 and play a critical role in regulating the activity of NK and CD8+ T cells. An association between polymorphisms in the NKC region, including the NKG2D gene and NKG2A promoter, and the risk of cancer has been previously described. The aim of this study was to analyze the association of polymorphisms in the NKC region with cutaneous melanoma in patients from southeastern Spain. Methods: Seven single-nucleotide polymorphisms (SNPs) in the NKG2D gene (NKC3,4,7,9,10,11,12), and one SNP in the NKG2A promoter (NKC17) were genotyped by a TaqMan 5′ Nuclease Assay in 233 melanoma patients and 200 matched healthy controls. Results: A linkage disequilibrium analysis of the SNPs performed in the NKC region revealed two blocks of haplotypes (Hb-1 and Hb-2) with 14 and seven different haplotype subtypes, respectively. The third most frequent haplotype from the block Hb-2—NK3 (CAT haplotype)—was significantly more frequent on melanoma patients than on healthy controls (p = 0.00009, Pc = 0.0006). No further associations were found when NKC SNPs were considered independently. Conclusions: Our results suggest an association between NKG2D polymorphisms and the risk of cutaneous malignant melanoma.

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Effect of dimethyl fumarate on lymphocyte subsets in patients with relapsing multiple sclerosis

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/2055217320918619 ◽

2020 ◽

Vol 6 (2) ◽

pp. 205521732091861 ◽

Cited By ~ 1

Author(s):

Guy Buckle ◽

Daniel Bandari ◽

Jeffrey Greenstein ◽

Mark Gudesblatt ◽

Bhupendra Khatri ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Confidence Interval ◽

Cd8 T Cells ◽

Lymphocyte Count ◽

Absolute Lymphocyte Count ◽

Dimethyl Fumarate ◽

T Cell Subsets ◽

Routine Practice ◽

Patients At Risk

Background In patients treated with dimethyl fumarate, absolute lymphocyte count decline typically occurs during the first year and then plateaus; early drops have been associated with the development of severe prolonged lymphopenia. Objective We investigated the effect of dimethyl fumarate on absolute lymphocyte counts and CD4+/CD8+ T cells in patients with relapsing–remitting multiple sclerosis treated with dimethyl fumarate in routine practice. Methods Lymphocyte data were collected via medical chart abstraction. Primary endpoint: change from baseline in absolute lymphocyte count and CD4+/CD8+ counts at 6‐month intervals following dimethyl fumarate initiation. Results Charts of 483 patients were abstracted and 476 patients included in the analysis. Mean baseline absolute lymphocyte count (2.23 × 109/l) decreased by ∼39% (95% confidence interval: –41.1 to –37.2) by month 6 and 44% (95% confidence interval: –46.6 to –42.1) by month 12. CD4+ and CD8+ T-cell subsets strongly correlated with absolute lymphocyte count, with greater decreases from baseline to 6 months vs 6–12 months, and in CD8+ vs CD4+ T cells. Prior natalizumab was not a risk factor for lymphopenia. Conclusion Dimethyl fumarate-associated decline in absolute lymphocyte count in the first 12 months correlated with decline in CD4+ and CD8+ T cells and was independent of prior natalizumab. Absolute lymphocyte count monitoring continues to be an effective strategy to identify patients at risk of prolonged lymphopenia.

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Glatiramer acetate-specific human CD8+ T cells: Increased IL-4 production in multiple sclerosis is reduced by glatiramer acetate treatment

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2006.07.014 ◽

2006 ◽

Vol 181 (1-2) ◽

pp. 133-140 ◽

Cited By ~ 11

Author(s):

Alexander Dressel ◽

Antje Vogelgesang ◽

Heinrich Brinkmeier ◽

Michael Mäder ◽

Frank Weber

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Glatiramer Acetate ◽

Cd8 T Cells

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4-1BB regulates NKG2D costimulation in human cord blood CD8+ T cells

Blood ◽

10.1182/blood-2007-01-069450 ◽

2008 ◽

Vol 111 (3) ◽

pp. 1378-1386 ◽

Cited By ~ 17

Author(s):

Young-June Kim ◽

Myung-Kwan Han ◽

Hal E. Broxmeyer

Keyword(s):

T Cells ◽

T Cell ◽

Cytotoxic Activity ◽

Cd8 T Cells ◽

Critical Role ◽

Cytotoxic T Cell ◽

Human Cord Blood ◽

Costimulatory Receptor ◽

Nkg2d Expression ◽

Tgf Β1

Abstract Ligation of NKG2D, a potent costimulatory receptor, can be either beneficial or detrimental to CD8+ cytotoxic T cell (CTL) responses. Factors for these diverse NKG2D effects remain elusive. In this study, we demonstrate that 4-1BB, another costimulatory receptor, is an essential regulator of NKG2D in CD8+ T cells. Costimulation of NKG2D caused down-modulation of NKG2D, but induced 4-1BB expression on the cell surface, even in the presence of TGF-β1, which inhibits 4-1BB expression. Resulting NKG2D−4-1BB+ cells were activated but still in an immature state with low cytotoxic activity. However, subsequent 4-1BB costimulation induced cytotoxic activity and restored down-modulated NKG2D. The cytotoxic activity and NKG2D expression induced by 4-1BB on NKG2D+4-1BB+ cells were refractory to TGF-β1 down-modulation. Such 4-1BB effects were enhanced by IL-12. In contrast, in the presence of IL-4, 4-1BB effects were abolished because IL-4 down-modulated NKG2D and 4-1BB expression in cooperation with TGF-β1, generating another CD8+ T-cell type lacking both NKG2D and 4-1BB. These NKG2D−4-1BB− cells were inert and unable to gain cytotoxic activity. Our results suggest that 4-1BB plays a critical role in protecting NKG2D from TGF-β1–mediated down-modulation. Co-expression of NKG2D and 4-1BB may represent an important biomarker for defining competency of tumor infiltrating CD8+ T cells.

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