scholarly journals Sirtuin 5 is Dispensable for CD8+ T Cell Effector and Memory Differentiation

2021 ◽  
Vol 9 ◽  
Author(s):  
Qianqian Duan ◽  
Jiying Ding ◽  
Fangfang Li ◽  
Xiaowei Liu ◽  
Yunan Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory Formation ◽  
Effector Function ◽  
Infection Model ◽  
Memory Differentiation ◽  
Multiple Levels ◽  
Protein Deacetylase ◽  
Cell Effector Function ◽  
Cell Effector

CD8+ T cell effector and memory differentiation is tightly controlled at multiple levels including transcriptional, metabolic, and epigenetic regulation. Sirtuin 5 (SIRT5) is a protein deacetylase mainly located at mitochondria, but it remains unclear whether SIRT5 plays key roles in regulating CD8+ T cell effector or memory formation. Herein, with adoptive transfer of Sirt5+/+ or Sirt5−/− OT-1 cells and acute Listeria monocytogenes infection model, we demonstrate that SIRT5 deficiency does not affect CD8+ T cell effector function and that SIRT5 is not required for CD8+ T cell memory formation. Moreover, the recall response of SIRT5 deficient memory CD8+ T cells is comparable with Sirt5+/+ memory CD8+ T cells. Together, these observations suggest that SIRT5 is dispensable for the effector function and memory differentiation of CD8+ T cells.

HPV16 E629-38-specific T cells kill cervical carcinoma cells despite partial evasion of T-cell effector function

2008 ◽  
Vol 122 (12) ◽  
pp. 2791-2799 ◽  
Author(s):  
Karen J. Thomas ◽  
Kelly L. Smith ◽  
Sarah J. Youde ◽  
Mererid Evans ◽  
Alison N. Fiander ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cervical Carcinoma ◽  
Effector Function ◽  
Carcinoma Cells ◽  
Cell Effector Function ◽  
Cell Effector

Endothelial induction of the T-cell chemokine CCL21 in T-cell autoimmune diseases

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 801-806 ◽  
Author(s):  
Kent W. Christopherson ◽  
Antoinette F. Hood ◽  
Jeffrey B. Travers ◽  
Heather Ramsey ◽  
Robert A. Hromas
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Skin Diseases ◽  
Effector Function ◽  
T Cell Migration ◽  
T Cell Infiltration ◽  
Secondary Lymphoid Organs ◽  
Cell Effector Function ◽  
Cell Effector

Abstract The signals that mediate T-cell infiltration during T-cell autoimmune diseases are poorly understood. The chemokine CCL21 (originally isolated by us and others as Exodus-2/6Ckine/SLC/TCA4) is highly potent and highly specific for stimulating T-cell migration. However, it is thought to be expressed only in secondary lymphoid organs, directing naive T cells to areas of antigen presentation. It is not thought to play a role in T-cell effector function during a normal immune response. In this study we tested the expression of T-cell chemokines and their receptors during T-cell autoimmune infiltrative skin diseases. By using immunohistology it was found that the expression of CCL21 but not CCL19 or 20 was highly induced in endothelial cells of T-cell autoimmune diseases. The receptor for CCL21, CCR7, was also found to be highly expressed on the infiltrating T cells, most of which expressed the memory CD45Ro phenotype. These data imply that the usual loss of CCL21 responsiveness in the normal development of memory T-cell effector function does not hold for autoimmune skin diseases.

scholarly journals Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets

2016 ◽  
Vol 213 (8) ◽  
pp. 1589-1608 ◽  
Author(s):  
Cindy S. Ma ◽  
Natalie Wong ◽  
Geetha Rao ◽  
Akira Nguyen ◽  
Danielle T. Avery ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
Cd4 T Cells ◽  
Clinical Manifestations ◽  
Effector Function ◽  
Cd4 T Cell ◽  
The Impact ◽  
Cell Effector Function ◽  
Cell Effector

Naive CD4+ T cells differentiate into specific effector subsets—Th1, Th2, Th17, and T follicular helper (Tfh)—that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4+ T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10–secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4+ T cell effector function in the settings of infection, vaccination, or immune dysregulation.

scholarly journals Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3673-3681 ◽  
Author(s):  
Philip O. Scumpia ◽  
Matthew J. Delano ◽  
Kindra M. Kelly-Scumpia ◽  
Jason S. Weinstein ◽  
James L. Wynn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Immune Dysfunction ◽  
Effector Function ◽  
Cd4 T Cell ◽  
Agonistic Antibody ◽  
Adaptive Immune ◽  
Cell Effector Function ◽  
Cell Effector

Abstract Apoptosis of CD4+ T cells and TH2 polarization are hallmarks of sepsis-induced immunoparalysis. In this study, we characterized sepsis-induced adaptive immune dysfunction and examined whether improving T-cell effector function can improve outcome to sepsis. We found that septic mice produced less antigen-specific T-cell–dependent IgM and IgG2a antibodies than sham-treated mice. As early as 24 hours after sepsis, CD4+ T cells proliferated poorly to T-cell receptor stimulation, despite normal responses to phorbol myristate acetate and ionomycin, and possessed decreased levels of CD3ζ. Five days following immunization, CD4+ T cells from septic mice displayed decreased antigen-specific proliferation and production of IL-2 and IFN-γ but showed no difference in IL-4, IL-5, or IL-10 production. Treatment of mice with anti-GITR agonistic antibody restored CD4+ T-cell proliferation, increased TH1 and TH2 cytokine production, partially prevented CD3ζ down-regulation, decreased bacteremia, and increased sepsis survival. Depletion of CD4+ T cells but not CD25+ regulatory T cells eliminated the survival benefit of anti-GITR treatment. These results indicate that CD4+ T-cell dysfunction is a key component of sepsis and that improving T-cell effector function may be protective against sepsis-associated immunoparalysis.

scholarly journals Enhancement of Suboptimal CD8 Cytotoxic T Cell Effector Function In Vivo Using Antigen-Specific CD80 Defective T Cells

2010 ◽  
Vol 186 (1) ◽  
pp. 291-304 ◽  
Author(s):  
Irina Puliaeva ◽  
Kateryna Soloviova ◽  
Maksym Puliaiev ◽  
Thomas Lang ◽  
Roman Puliaev ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Effector Function ◽  
Cytotoxic T Cell ◽  
Cell Effector Function ◽  
Cell Effector

scholarly journals CD28 Co-Stimulus Achieves Superior CAR T Cell Effector Function against Solid Tumors Than 4-1BB Co-Stimulus

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1050
Author(s):  
Ana Textor ◽  
Laura Grunewald ◽  
Kathleen Anders ◽  
Anika Klaus ◽  
Silke Schwiebert ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Effector Function ◽  
Human Neuroblastoma ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Cell Effector Function ◽  
Cell Effector

Spacer or co-stimulatory components in chimeric antigen receptor (CAR) design influence CAR T cell effector function. Few preclinical mouse models optimally support CAR candidate pre-selection for clinical development. Here we use a model in which murine CAR T cells can be exploited with human tumor xenografts. This mouse-in-mouse approach avoids limitations caused by species-specific factors crucial for CAR T cell survival, trafficking and function. We compared trafficking, expansion and tumor control for T cells expressing different CAR construct designs targeting two antigens (L1CAM or HER2), structurally identical except for spacer (long or short) or co-stimulatory (4-1BB or CD28) domains to be evaluated. Using monoclonal, murine-derived L1CAM-specific CAR T cells in Rag-/- mice harboring established xenografted tumors from a human neuroblastoma cell line revealed a clear superiority in CAR T cell trafficking using CD28 co-stimulation. L1CAM-targeting short spacer-CD28/ζ CAR T cells expanded the most at the tumor site and induced initial tumor regression. Treating patient-derived neuroblastoma xenografts with human L1CAM-targeting CAR T cells confirmed the superiority of CD28 co-stimulus. CD28 superiority was also demonstrated with HER2-specific CAR T cells (targeting ovarian carcinoma xenografts). Our findings encourage incorporating CD28 signaling into CAR design for adoptive T cell treatment of solid tumors.

Interleukin-10 promotes the maintenance of antitumor CD8+ T-cell effector function in situ

Blood ◽  
2001 ◽  
Vol 98 (7) ◽  
pp. 2143-2151 ◽  
Author(s):  
Shin-ichiro Fujii ◽  
Kanako Shimizu ◽  
Takashi Shimizu ◽  
Michael T. Lotze
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Interleukin 10 ◽  
Effector Function ◽  
Cytotoxic T Cell ◽  
Cell Effector Function ◽  
Cell Effector

Interleukin-10 (IL-10) is a multifunctional cytokine that can exert suppressive and stimulatory effects on T cells. It was investigated whether IL-10 could serve as an immunostimulant for specific CD8+ cytotoxic T cell (CTL) in vivo after vaccination and, if so, under what conditions. In tumor prevention models, administration of IL-10 before, or soon after, peptide-pulsed primary dendritic cell immunization resulted in immune suppression and enhanced tumor progression. Injection of IL-10, however, just after a booster vaccine significantly enhanced antitumor immunity and vaccine efficacy. Analysis of spleen cells derived from these latter animals 3 weeks after IL-10 treatment revealed that the number of CD8+CD44hi CD122+ T cells had increased and that antigen-specific proliferation in vitro was enhanced. Although cytotoxicity assays did not support differences between the various treatment groups, 2 more sensitive assays measuring antigen-specific interferon-γ production at the single-cell level demonstrated increases in the number of antigen-specific responder T cells in animals in the vaccine/IL-10 treatment group. Thus, IL-10 may maintain the number of antitumor CD8+ T cells. In adoptive transfer studies, the ability of IL-10 to maintain CTL function could be enhanced by the depletion of CD4+ T cells. This suggests that IL-10 mediates contrasting effects on both CD4+ and CD8+ T cells that result in either immune dampening or immune potentiation in situ, respectively. Appreciation of this dichotomy in IL-10 immunobiology may allow for the design of more effective cancer vaccines designed to activate and maintain specific CD8+ T-cell effector function in situ.

Bet v 1–specific T-cell receptor/forkhead box protein 3 transgenic T cells suppress Bet v 1–specific T-cell effector function in an activation-dependent manner

2011 ◽  
Vol 127 (1) ◽  
pp. 238-245.e3 ◽  
Author(s):  
Klaus G. Schmetterer ◽  
Daniela Haiderer ◽  
Victoria M. Leb-Reichl ◽  
Alina Neunkirchner ◽  
Beatrice Jahn-Schmid ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Effector Function ◽  
Dependent Manner ◽  
Bet V 1 ◽  
Forkhead Box ◽  
Cell Effector Function ◽  
Cell Effector

scholarly journals Macrophages Control the Bioavailability of Vitamin D and Vitamin D-Regulated T Cell Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Daniel Villalba Lopez ◽  
Fatima A. H. Al-Jaberi ◽  
Anders Woetmann ◽  
Niels Ødum ◽  
Charlotte Menné Bonefeld ◽  
...  
Keyword(s):  
Vitamin D ◽  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
T Cell Responses ◽  
Effector Function ◽  
M1 Macrophages ◽  
Cell Responses ◽  
Cell Effector Function ◽  
Cell Effector

The active form of vitamin D3 (1,25(OH)2D3) has a great impact on T cell effector function. Thus, 1,25(OH)2D3 promotes T helper 2 (Th2) and regulatory T (Treg) cell function and concomitantly inhibits Th1 and Th17 cell function. Thus, it is believed that vitamin D exerts anti-inflammatory effects. However, vitamin D binding protein (DBP) strongly binds both 1,25(OH)2D3 and the precursor 25(OH)D3, leaving only a minor fraction of vitamin D in the free, bioavailable form. Accordingly, DBP in physiological concentrations would be expected to block the effect of vitamin D on T cells and dendritic cells. In the present study, we show that pro-inflammatory, monocyte-derived M1 macrophages express very high levels of the 25(OH)D-1α-hydroxylase CYP27B1 that enables them to convert 25(OH)D3 into 1,25(OH)2D3 even in the presence of physiological concentrations of DBP. Co-cultivation of M1 macrophages with T cells allows them to overcome the sequestering of 25(OH)D3 by DBP and to produce sufficient levels of 1,25(OH)2D3 to affect T cell effector function. This study suggests that in highly inflammatory conditions, M1 macrophages can produce sufficient levels of 1,25(OH)2D3 to modify T cell responses and thereby reduce T cell-mediated inflammation via a vitamin D-mediated negative feed-back loop.

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