scholarly journals Deletion of the mitochondria-shaping protein Opa1 during early thymocyte maturation impacts mature memory T cell metabolism

2021 ◽  
Author(s):  
Mauro Corrado ◽  
Dijana Samardžić ◽  
Marta Giacomello ◽  
Nisha Rana ◽  
Erika L. Pearce ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Effector Memory ◽  
Long Term Memory ◽  
Memory T Cell ◽  
T Cell Function

AbstractOptic atrophy 1 (OPA1), a mitochondria-shaping protein controlling cristae biogenesis and respiration, is required for memory T cell function, but whether it affects intrathymic T cell development is unknown. Here we show that OPA1 is necessary for thymocyte maturation at the double negative (DN)3 stage when rearrangement of the T cell receptor β (Tcrβ) locus occurs. By profiling mitochondrial function at different stages of thymocyte maturation, we find that DN3 cells rely on oxidative phosphorylation. Consistently, Opa1 deletion during early T cell development impairs respiration of DN3 cells and reduces their number. Opa1-deficient DN3 cells indeed display stronger TCR signaling and are more prone to cell death. The surviving Opa1−/− thymocytes that reach the periphery as mature T cells display an effector memory phenotype even in the absence of antigenic stimulation but are unable to generate metabolically fit long-term memory T cells. Thus, mitochondrial defects early during T cell development affect mature T cell function.

scholarly journals Acidity suppresses T cell function and increases memory T cell development

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Hao Wu ◽  
Veronica Estrella ◽  
Pedro Enriquez‐Navas ◽  
Dominique Abrahams ◽  
Arig Ibrahim‐Hashim ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
T Cell Development ◽  
Cell Development ◽  
Memory T Cell ◽  
T Cell Function

scholarly journals Serine Phosphorylation of SLP76 Is Dispensable for T Cell Development but Modulates Helper T Cell Function

PLoS ONE ◽  
2017 ◽  
Vol 12 (1) ◽  
pp. e0170396 ◽  
Author(s):  
Victor H. Navas ◽  
Céline Cuche ◽  
Andres Alcover ◽  
Vincenzo Di Bartolo
Keyword(s):  
T Cell ◽  
Cell Function ◽  
T Cell Development ◽  
Cell Development ◽  
Serine Phosphorylation ◽  
Helper T Cell ◽  
T Cell Function

scholarly journals Interleukin-7 Regulates Bim Proapoptotic Activity in Peripheral T-Cell Survival

2009 ◽  
Vol 30 (3) ◽  
pp. 590-600 ◽  
Author(s):  
Wen Qing Li ◽  
Tad Guszczynski ◽  
Julie A. Hixon ◽  
Scott K. Durum
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
T Cell Development ◽  
Cell Development ◽  
Effector Memory ◽  
Intracellular Location ◽  
Interleukin 7 ◽  
Peripheral T Cells ◽  
T Cell Survival

ABSTRACT Interleukin-7 (IL-7) is critical for T-cell development and peripheral T-cell homeostasis. The survival of pro-T cells and mature T cells requires IL-7. The survival function of IL-7 is accomplished partly through induction of the antiapoptotic protein Bcl-2 and inhibition of proapoptotic proteins Bax and Bad. We show here that the proapoptotic protein Bim, a BH3-only protein belonging to the Bcl-2 family, also plays a role in peripheral T-cell survival. Deletion of Bim partially protected an IL-7-dependent T-cell line and peripheral T cells, especially cells with an effector memory phenotype, from IL-7 deprivation. However, T-cell development in the thymus was not restored in IL-7−/− Rag2−/− mice reconstituted with Bim−/− bone marrow. IL-7 withdrawal altered neither the intracellular location of Bim, which was constitutively mitochondrial, nor its association with Bcl-2; however, a reduction in its association with the prosurvival protein Mcl-1 was observed. IL-7 withdrawal did not increase Bim mRNA or protein expression but did induce changes in the isoelectric point of BimEL and its reactivity with an antiphosphoserine antibody. Our findings suggest that the maintenance of peripheral T cells by IL-7 occurs partly through inhibition of Bim activity at the posttranslational level.

scholarly journals Inactivation of c-Cbl Reverses Neonatal Lethality and T Cell Developmental Arrest of SLP-76–deficient Mice

2004 ◽  
Vol 200 (1) ◽  
pp. 25-34 ◽  
Author(s):  
Y. Jeffrey Chiang ◽  
Connie L. Sommers ◽  
Martha S. Jordan ◽  
Hua Gu ◽  
Lawrence E. Samelson ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Adaptor Protein ◽  
Premature Death ◽  
Cell Receptor ◽  
Cell Development ◽  
Neonatal Lethality ◽  
Deficient Mice

c-Cbl is an adaptor protein that negatively regulates signal transduction events involved in thymic-positive selection. To further characterize the function of c-Cbl in T cell development, we analyzed the effect of c-Cbl inactivation in mice deficient in the scaffolding molecule SLP-76. SLP-76–deficient mice show a high frequency of neonatal lethality; and in surviving mice, T cell development is blocked at the DN3 stage. Inactivation of c-cbl completely reversed the neonatal lethality seen in SLP-76–deficient mice and partially reversed the T cell development arrest in these mice. SLP-76−/− Cbl−/− mice exhibited marked expansion of polarized T helper type (Th)1 and Th2 cell peripheral CD4+ T cells, lymphoid infiltrates of parenchymal organs, and premature death. This rescue of T cell development is T cell receptor dependent because it does not occur in recombination activating gene 2−/− SLP-76−/− Cbl−/− triple knockout mice. Analysis of the signal transduction properties of SLP-76−/− Cbl−/− T cells reveals a novel SLP-76– and linker for activation of T cells–independent pathway of extracellular signal–regulated kinase activation, which is normally down-regulated by c-Cbl.

CD3 limits the efficacy of TCR gene therapy in vivo

Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. 3528-3537 ◽  
Author(s):  
Maryam Ahmadi ◽  
Judith W. King ◽  
Shao-An Xue ◽  
Cécile Voisine ◽  
Angelika Holler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Cell Receptor ◽  
Surface Expression ◽  
T Cell Function ◽  
Engineered T Cells ◽  
Rate Limiting

Abstract The function of T-cell receptor (TCR) gene modified T cells is dependent on efficient surface expression of the introduced TCR α/β heterodimer. We tested whether endogenous CD3 chains are rate-limiting for TCR expression and antigen-specific T-cell function. We show that co-transfer of CD3 and TCR genes into primary murine T cells enhanced TCR expression and antigen-specific T-cell function in vitro. Peptide titration experiments showed that T cells expressing introduced CD3 and TCR genes recognized lower concentration of antigen than T cells expressing TCR only. In vivo imaging revealed that TCR+CD3 gene modified T cells infiltrated tumors faster and in larger numbers, which resulted in more rapid tumor elimination compared with T cells modified by TCR only. After tumor clearance, TCR+CD3 engineered T cells persisted in larger numbers than TCR-only T cells and mounted a more effective memory response when rechallenged with antigen. The data demonstrate that provision of additional CD3 molecules is an effective strategy to enhance the avidity, anti-tumor activity and functional memory formation of TCR gene modified T cells in vivo.

scholarly journals Circulating HLA-DR+CD4+ effector memory T cells resistant to CCR5 and PD-L1 mediated suppression compromise regulatory T cell function in tuberculosis

2018 ◽  
Vol 14 (9) ◽  
pp. e1007289 ◽  
Author(s):  
Asma Ahmed ◽  
Vasista Adiga ◽  
Soumya Nayak ◽  
J. Anto Jesuraj Uday Kumar ◽  
Chirag Dhar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cell ◽  
Cell Function ◽  
Memory T Cells ◽  
Effector Memory ◽  
Effector Memory T Cells ◽  
T Cell Function ◽  
Hla Dr

scholarly journals The Effects of TLR Activation on T-Cell Development and Differentiation

2012 ◽  
Vol 2012 ◽  
pp. 1-32 ◽  
Author(s):  
Bo Jin ◽  
Tao Sun ◽  
Xiao-Hong Yu ◽  
Ying-Xiang Yang ◽  
Anthony E. T. Yeo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Development ◽  
Cell Receptor ◽  
Treg Cells ◽  
Cell Development ◽  
T Cell Subsets ◽  
Follicular Helper ◽  
Development And Differentiation

Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.

scholarly journals Separation of Notch1 Promoted Lineage Commitment and Expansion/Transformation in Developing T Cells

2001 ◽  
Vol 194 (1) ◽  
pp. 99-106 ◽  
Author(s):  
David Allman ◽  
Fredrick G. Karnell ◽  
Jennifer A. Punt ◽  
Sonia Bakkour ◽  
Lanwei Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Surface Proteins ◽  
Lineage Commitment ◽  
Double Positive ◽  
Hematopoietic Stem ◽  
Multipotent Progenitor Cells

Notch1 signaling is required for T cell development. We have previously demonstrated that expression of a dominant active Notch1 (ICN1) transgene in hematopoietic stem cells (HSCs) leads to thymic-independent development of CD4+CD8+ double-positive (DP) T cells in the bone marrow (BM). To understand the function of Notch1 in early stages of T cell development, we assessed the ability of ICN1 to induce extrathymic T lineage commitment in BM progenitors from mice that varied in their capacity to form a functional pre-T cell receptor (TCR). Whereas mice repopulated with ICN1 transduced HSCs from either recombinase deficient (Rag-2−/−) or Src homology 2 domain–containing leukocyte protein of 76 kD (SLP-76)−/− mice failed to develop DP BM cells, recipients of ICN1-transduced Rag-2−/− progenitors contained two novel BM cell populations indicative of pre-DP T cell development. These novel BM populations are characterized by their expression of CD3ε and pre-Tα mRNA and the surface proteins CD44 and CD25. In contrast, complementation of Rag-2−/− mice with a TCRβ transgene restored ICN1-induced DP development in the BM within 3 wk after BM transfer (BMT). At later time points, this population selectively and consistently gave rise to T cell leukemia. These findings demonstrate that Notch signaling directs T lineage commitment from multipotent progenitor cells; however, both expansion and leukemic transformation of this population are dependent on T cell–specific signals associated with development of DP thymocytes.

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 Requirement of dendritic cells and B cells in the clonal deletion of Mls-reactive T cells in the thymus.

1991 ◽  
Vol 173 (3) ◽  
pp. 539-547 ◽  
Author(s):  
O Mazda ◽  
Y Watanabe ◽  
J Gyotoku ◽  
Y Katsura
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Clonal Deletion ◽  
Fetal Thymus ◽  
Effector Cells

The present study was performed to identify cells responsible for the elimination of T cells reactive with minor lymphocyte-stimulating (Mls) antigens during T cell development. Experiments were carried out in a fetal thymus organ culture (FTOC) system. To examine the tolerance-inducing activity, various populations of cells from adult CBA/J (Mls-1a) mice were injected into deoxyguanosine (dGuo)-treated FTOC of C3H/He (Mls-1b) mice with a microinjector, and 2 d later, the thymus lobes were injected with fetal thymus cells from C3H/He mice as T cell precursors. After 14 d of cultivation, cells were harvested and assayed for the expression of the T cell receptor V beta 6 element. The absence or marked reduction of T cells expressing V beta 6 at high levels (V beta 6high) was regarded as indicating the deletion of Mls-1a-reactive T cells. T cell-depleted populations of thymic as well as splenic cells from CBA/J mice were able to induce clonal deletion. Further characterization of the effector cells was carried out by fractionating the spleen cells before injecting them into dGuo-FTOC. None of the dish-adherent population, dish-nonadherent population, or purified B cells alone were able to induce clonal deletion, whereas the addition of purified B cells to adherent cells restored tolerance inducibility. It was further shown that a combination of CBA/J B cells and C3H/He dendritic cells was effective in eliminating Mls-reactive clones. These results indicate that for the deletion of clones reactive with Mls antigens during T cell development in the thymus, both DC and B cells are required.

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