scholarly journals miR-23∼27∼24 clusters control effector T cell differentiation and function

2016 ◽  
Vol 213 (2) ◽  
pp. 235-249 ◽  
Author(s):  
Sunglim Cho ◽  
Cheng-Jang Wu ◽  
Tomoharu Yasuda ◽  
Leilani O. Cruz ◽  
Aly Azeem Khan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Biology ◽  
Cell Function ◽  
Mirna Family ◽  
Biological Effects ◽  
Effector T Cell ◽  
T Cell Biology ◽  
Mirna Clusters ◽  
And Function

Coordinated repression of gene expression by evolutionarily conserved microRNA (miRNA) clusters and paralogs ensures that miRNAs efficiently exert their biological impact. Combining both loss- and gain-of-function genetic approaches, we show that the miR-23∼27∼24 clusters regulate multiple aspects of T cell biology, particularly helper T (Th) 2 immunity. Low expression of this miRNA family confers proper effector T cell function at both physiological and pathological settings. Further studies in T cells with exaggerated regulation by individual members of the miR-23∼27∼24 clusters revealed that miR-24 and miR-27 collaboratively limit Th2 responses through targeting IL-4 and GATA3 in both direct and indirect manners. Intriguingly, although overexpression of the entire miR-23 cluster also negatively impacts other Th lineages, enforced expression of miR-24, in contrast to miR-23 and miR-27, actually promotes the differentiation of Th1, Th17, and induced regulatory T cells, implying that under certain conditions, miRNA families can fine tune the biological effects of their regulation by having individual members antagonize rather than cooperate with each other. Together, our results identify a miRNA family with important immunological roles and suggest that tight regulation of miR-23∼27∼24 clusters in T cells is required to maintain optimal effector function and to prevent aberrant immune responses.

scholarly journals Phospholipase Cγ1 is essential for T cell development, activation, and tolerance

2010 ◽  
Vol 207 (2) ◽  
pp. 309-318 ◽  
Author(s):  
Guoping Fu ◽  
Yuhong Chen ◽  
Mei Yu ◽  
Andy Podd ◽  
James Schuman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Biology ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Phospholipase Cγ1 ◽  
T Cell Biology ◽  
Single Positive ◽  
And Function

Phospholipase Cγ1 (PLCγ1) is an important signaling effector of T cell receptor (TCR). To investigate the role of PLCγ1 in T cell biology, we generated and examined mice with T cell–specific deletion of PLCγ1. We demonstrate that PLCγ1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-κB. Importantly, PLCγ1 deficiency impairs the development and function of FoxP3+ regulatory T cells, causing inflammatory/autoimmune symptoms. Therefore, PLCγ1 is essential for T cell development, activation, and tolerance.

scholarly journals The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function

2020 ◽  
Author(s):  
Bergithe E Oftedal ◽  
Stefano Maio ◽  
Adam Handel ◽  
Madeleine PJ White ◽  
Duncan Howie ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Biology ◽  
Cell Activation ◽  
T Cell Biology ◽  
Th2 Polarization ◽  
Cell Stress Response ◽  
And Function ◽  
Induced Changes

AbstractT cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. In the absence of the eukaryotic type II chaperonin complex, CCT, T cell activation induced changes in the proteome are compromised including the formation of nuclear actin filaments and the formation of a normal cell stress response. Consequently, thymocyte maturation and selection, and T cell homeostatic maintenance and receptor-mediated activation are severely impaired. Additionally, Th2 polarization digresses in the absence of CCT-controlled protein folding resulting paradoxically in continued IFN-γ expression. As a result, CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems. These findings thus demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity.

scholarly journals Chimeric non-antigen receptors in T cell-based cancer therapy

2021 ◽  
Vol 9 (8) ◽  
pp. e002628
Author(s):  
Jitao Guo ◽  
Andrew Kent ◽  
Eduardo Davila
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Therapy ◽  
Tumor Antigen ◽  
Cell Function ◽  
Antigen Recognition ◽  
Cancer Therapies ◽  
Antigen Receptors ◽  
Natural Ligands ◽  
And Function

Adoptively transferred T cell-based cancer therapies have shown incredible promise in treatment of various cancers. So far therapeutic strategies using T cells have focused on manipulation of the antigen-recognition machinery itself, such as through selective expression of tumor-antigen specific T cell receptors or engineered antigen-recognition chimeric antigen receptors (CARs). While several CARs have been approved for treatment of hematopoietic malignancies, this kind of therapy has been less successful in the treatment of solid tumors, in part due to lack of suitable tumor-specific targets, the immunosuppressive tumor microenvironment, and the inability of adoptively transferred cells to maintain their therapeutic potentials. It is critical for therapeutic T cells to overcome immunosuppressive environmental triggers, mediating balanced antitumor immunity without causing unwanted inflammation or autoimmunity. To address these hurdles, chimeric receptors with distinct signaling properties are being engineered to function as allies of tumor antigen-specific receptors, modulating unique aspects of T cell function without directly binding to antigen themselves. In this review, we focus on the design and function of these chimeric non-antigen receptors, which fall into three broad categories: ‘inhibitory-to-stimulatory’ switch receptors that bind natural ligands, enhanced stimulatory receptors that interact with natural ligands, and synthetic receptor-ligand pairs. Our intent is to offer detailed descriptions that will help readers to understand the structure and function of these receptors, as well as inspire development of additional novel synthetic receptors to improve T cell-based cancer therapy.

scholarly journals CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

2009 ◽  
Vol 206 (2) ◽  
pp. 421-434 ◽  
Author(s):  
Randall H. Friedline ◽  
David S. Brown ◽  
Hai Nguyen ◽  
Hardy Kornfeld ◽  
JinHee Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Cytotoxic T Lymphocyte ◽  
Critical Role ◽  
Lymphoproliferative Disease ◽  
In Trans ◽  
And Function

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3+ regulatory T cells. CTLA-4–deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4–deficient and –sufficient bone marrow (BM)–derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4−/− T cells in trans by CTLA-4–sufficient T cells is a reversible process that requires the persistent presence of FOXP3+ regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3+ regulatory T cell function in vivo.

scholarly journals T Cell Receptor Specificity Is Critical for the Development of Epidermal γδ T Cells

2001 ◽  
Vol 194 (10) ◽  
pp. 1473-1483 ◽  
Author(s):  
Isabel Ferrero ◽  
Anne Wilson ◽  
Friedrich Beermann ◽  
Werner Held ◽  
H. Robson MacDonald
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Biology ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Wild Type ◽  
Normal Numbers ◽  
T Cell Biology

A particular feature of γδ T cell biology is that cells expressing T cell receptor (TCR) using specific Vγ/Vδ segments are localized in distinct epithelial sites, e.g., in mouse epidermis nearly all γδ T cells express Vγ3/Vδ1. These cells, referred to as dendritic epidermal T cells (DETC) originate from fetal Vγ3+ thymocytes. The role of γδ TCR specificity in DETC's migration/localization to the skin has remained controversial. To address this issue we have generated transgenic (Tg) mice expressing a TCR δ chain (Vδ6.3-Dδ1-Dδ2-Jδ1-Cδ), which can pair with Vγ3 in fetal thymocytes but is not normally expressed by DETC. In wild-type (wt) Vδ6.3Tg mice DETC were present and virtually all of them express Vδ6.3. However, DETC were absent in TCR-δ−/− Vδ6.3Tg mice, despite the fact that Vδ6.3Tg γδ T cells were present in normal numbers in other lymphoid and nonlymphoid tissues. In wt Vδ6.3Tg mice, a high proportion of in-frame Vδ1 transcripts were found in DETC, suggesting that the expression of an endogenous TCR-δ (most probably Vδ1) was required for the development of Vδ6.3+ epidermal γδ T cells. Collectively our data demonstrate that TCR specificity is essential for the development of γδ T cells in the epidermis. Moreover, they show that the TCR-δ locus is not allelically excluded.

Interferon- Activates Multiple STAT Proteins and Upregulates Proliferation-Associated IL-2R, c-myc, and pim-1 Genes in Human T Cells

Blood ◽  
1999 ◽  
Vol 93 (6) ◽  
pp. 1980-1991 ◽  
Author(s):  
Sampsa Matikainen ◽  
Timo Sareneva ◽  
Tapani Ronni ◽  
Anne Lehtonen ◽  
Päivi J. Koskinen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Biology ◽  
Interleukin 2 ◽  
T Cell Proliferation ◽  
Stat Proteins ◽  
Human T Cells ◽  
T Cell Biology ◽  
Cytokine Stimulation

Interferon- (IFN-) is a pleiotropic cytokine that has antiviral, antiproliferative, and immunoregulatory functions. There is increasing evidence that IFN- has an important role in T-cell biology. We have analyzed the expression ofIL-2R, c-myc, and pim-1 genes in anti-CD3–activated human T lymphocytes. The induction of these genes is associated with interleukin-2 (IL-2)–induced T-cell proliferation. Treatment of T lymphocytes with IFN-, IL-2, IL-12, and IL-15 upregulated IL-2R, c-myc, andpim-1 gene expression. IFN- also sensitized T cells to IL-2–induced proliferation, further suggesting that IFN- may be involved in the regulation of T-cell mitogenesis. When we analyzed the nature of STAT proteins capable of binding to IL-2R,pim-1, and IRF-1 GAS elements after cytokine stimulation, we observed IFN-–induced binding of STAT1, STAT3, and STAT4, but not STAT5 to all of these elements. Yet, IFN- was able to activate binding of STAT5 to the high-affinity IFP53 GAS site. IFN- enhanced tyrosine phosphorylation of STAT1, STAT3, STAT4, STAT5a, and STAT5b. IL-12 induced STAT4 and IL-2 and IL-15 induced STAT5 binding to the GAS elements. Taken together, our results suggest that IFN-, IL-2, IL-12, and IL-15 have overlapping activities on human T cells. These findings thus emphasize the importance of IFN- as a T-cell regulatory cytokine.

FoxP3+Regulatory T Cells Suppress Effector T-Cell Function at Pathologic Site in Miliary Tuberculosis

2009 ◽  
Vol 179 (11) ◽  
pp. 1061-1070 ◽  
Author(s):  
Prabhat K. Sharma ◽  
Pradip K. Saha ◽  
Amar Singh ◽  
Surendra K. Sharma ◽  
Balaram Ghosh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Miliary Tuberculosis ◽  
Effector T Cell ◽  
T Cell Function

scholarly journals Antigen-Specific Inhibition of Effector T Cell Function in Humans after Injection of Immature Dendritic Cells

2001 ◽  
Vol 193 (2) ◽  
pp. 233-238 ◽  
Author(s):  
Madhav V. Dhodapkar ◽  
Ralph M. Steinman ◽  
Joseph Krasovsky ◽  
Christian Munz ◽  
Nina Bhardwaj
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Specific Inhibition ◽  
Killer Activity ◽  
Effector T Cell ◽  
T Cell Function ◽  
Cell Immunity

Immunostimulatory properties of dendritic cells (DCs) are linked to their maturation state. Injection of mature DCs rapidly enhances antigen-specific CD4+ and CD8+ T cell immunity in humans. Here we describe the immune response to a single injection of immature DCs pulsed with influenza matrix peptide (MP) and keyhole limpet hemocyanin (KLH) in two healthy subjects. In contrast to prior findings using mature DCs, injection of immature DCs in both subjects led to the specific inhibition of MP-specific CD8+ T cell effector function in freshly isolated T cells and the appearance of MP-specific interleukin 10–producing cells. When pre- and postimmunization T cells were boosted in culture, there were greater numbers of MP-specific major histocompatibility complex tetramer-binding cells after immunization, but these had reduced interferon γ production and lacked killer activity. These data demonstrate the feasibility of antigen-specific inhibition of effector T cell function in vivo in humans and urge caution with the use of immature DCs when trying to enhance tumor or microbial immunity.

scholarly journals Targeting of Cdc42 GTPase in regulatory T cells unleashes anti-tumor T cell immunity

2021 ◽  
Author(s):  
Khalid W Kalim ◽  
Jun-Qi Yang ◽  
Mark Wunderlich ◽  
Vishnu Modur ◽  
Phuong Nguyen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cell ◽  
Cell Function ◽  
Treg Cells ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Plasticity ◽  
Effector T Cell ◽  
Cell Immunity

Regulatory T (Treg) cells play an important role in maintaining immune tolerance through inhibiting effector T cell function. In the tumor microenvironment, Treg cells are utilized by tumor cells to counteract effector T cell-mediated tumor killing. Targeting Treg cells may thus unleash the anti-tumor activity of effector T cells. While systemic depletion of Treg cells can cause excessive effector T cell responses and subsequent autoimmune diseases, controlled targeting of Treg cells may benefit cancer patients. Here we show that Treg cell-specific heterozygous deletion or pharmacological targeting of Cdc42 GTPase does not affect Treg cell numbers but induces Treg cell plasticity, leading to anti-tumor T cell immunity without detectable autoimmune reactions. Cdc42 targeting potentiates an immune checkpoint blocker anti-PD-1 antibody-mediated T cell response against mouse and human tumors. Mechanistically, Cdc42 targeting induces Treg cell plasticity and unleashes anti-tumor T cell immunity through carbonic anhydrase I-mediated pH changes. Thus, rational targeting of Cdc42 in Treg cells holds therapeutic promises in cancer immunotherapy.

scholarly journals The New Old CD8+ T Cells in the Immune Paradox of Pregnancy

2021 ◽  
Vol 12 ◽  
Author(s):  
Lilja Hardardottir ◽  
Maria Victoria Bazzano ◽  
Laura Glau ◽  
Luca Gattinoni ◽  
Angela Köninger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Biology ◽  
Immune Cell ◽  
Cd8 T Cell ◽  
Therapeutic Interventions ◽  
Effector Memory ◽  
Pregnant Uterus ◽  
T Cell Biology

CD8+ T cells are the most frequent T cell population in the immune cell compartment at the feto-maternal interface. Due to their cytotoxic potential, the presence of CD8+ T cells in the immune privileged pregnant uterus has raised considerable interest. Here, we review our current understanding of CD8+ T cell biology in the uterus of pregnant women and discuss this knowledge in relation to a recently published immune cell Atlas of human decidua. We describe how the expansion of CD8+ T cells with an effector memory phenotype often presenting markers of exhaustion is critical for a successful pregnancy, and host defense towards pathogens. Moreover, we review new evidence on the presence of long-lasting immunological memory to former pregnancies and discuss its impact on prospective pregnancy outcomes. The formation of fetal-specific memory CD8+ T cell subests in the uterus, in particular of tissue resident, and stem cell memory cells requires further investigation, but promises interesting results to come. Advancing the knowledge of CD8+ T cell biology in the pregnant uterus will be pivotal for understanding not only tissue-specific immune tolerance but also the etiology of complications during pregnancy, thus enabling preventive or therapeutic interventions in the future.

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