scholarly journals Mevalonate metabolism–dependent protein geranylgeranylation regulates thymocyte egress

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
Xingrong Du ◽  
Hu Zeng ◽  
Shaofeng Liu ◽  
Cliff Guy ◽  
Yogesh Dhungana ◽  
...  
Keyword(s):  
T Cell ◽  
Similar Process ◽  
Immune Homeostasis ◽  
T Cell Homeostasis ◽  
Protein Prenylation ◽  
Critical Determinant ◽  
Cell Homeostasis ◽  
Signaling Mechanism ◽  
Downstream Signaling

Thymocyte egress is a critical determinant of T cell homeostasis and adaptive immunity. Despite the roles of G protein–coupled receptors in thymocyte emigration, the downstream signaling mechanism remains poorly defined. Here, we report the discrete roles for the two branches of mevalonate metabolism–fueled protein prenylation pathway in thymocyte egress and immune homeostasis. The protein geranylgeranyltransferase Pggt1b is up-regulated in single-positive thymocytes, and loss of Pggt1b leads to marked defects in thymocyte egress and T cell lymphopenia in peripheral lymphoid organs in vivo. Mechanistically, Pggt1b bridges sphingosine-1-phosphate and chemokine-induced migratory signals with the activation of Cdc42 and Pak signaling and mevalonate-dependent thymocyte trafficking. In contrast, the farnesyltransferase Fntb, which mediates a biochemically similar process of protein farnesylation, is dispensable for thymocyte egress but contributes to peripheral T cell homeostasis. Collectively, our studies establish context-dependent effects of protein prenylation and unique roles of geranylgeranylation in thymic egress and highlight that the interplay between cellular metabolism and posttranslational modification underlies immune homeostasis.

scholarly journals SHIP-1 Regulates the Differentiation and Function of Tregs via Inhibiting mTORC1 Activity

2022 ◽  
Author(s):  
Zuochen Du ◽  
Jinzhi Wang ◽  
Di Yang ◽  
Xiaoyu Sun ◽  
Lu Huang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Metabolism ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Signaling Mechanism ◽  
Suppressive Function ◽  
And Function

Abstract Cell metabolism is crucial for orchestrating the differentiation and function of regulatory T cells (Tregs). However, the underlying signaling mechanism that coordinates cell metabolism to regulate Treg activity is not completely understood. As a pivotal molecule in lipid metabolism, the role of SHIP-1 has been studied extensively in B cells and CD4 T cells, yet its regulatory role in Tregs remains unknown. In this study, we generated “SHIP-1 KO mice” that have SHIP-1 specifically deleted in regulatory T cells by crossing Foxp3YFP-cre mice with SHIP-1fl/fl mice. Surprisingly, SHIP-1 KO mice had severe autoimmunity with increased Tregs in the thymus and disrupted peripheral T cell homeostasis. Mechanistically, CD4Cre SHIP-1flox/flox mice were found to have increased Treg precursors and SHIP-1 KO Tregs had reduced migration and stability, which caused decreased Tregs in the spleen. Additionally, the suppressive function of Tregs from SHIP-1 KO mice was diminished, along with their promotion of anti-tumor immunity. Interestingly, the PI3K-mTORC1, but not mTORC2, signaling axis was enhanced in SHIP-1 KO Tregs. In vivo treatment of SHIP-1 KO mice with rapamycin rescued the abnormal Treg percentages and peripheral T cell homeostasis, as well as Treg suppressive function. Furthermore, the treatment of wild-type mice with SHIP-1 inhibitor enhanced anti-tumor activity. Our study has revealed a previously unrecognized underlying function of SHIP-1 in Tregs, which highlights the SHIP-1-PI3K-mTORC1 axis that regulates Treg differentiation and function.

Selective Disruption of PU.1 in Mature Dendritic Cells Affects Their Tissue Distribution and T Cell Homeostasis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 518-518
Author(s):  
Tadafumi Iino ◽  
Hiromi Iwasaki ◽  
Kentaro Kohno ◽  
Shin-ichi Mizuno ◽  
Yojiro Arinobu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
T Cell Response ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Hematopoietic Stem

Abstract Abstract 518 PU.1, a hematopoietic transcription factor, is indispensable for development of conventional dendritic cells (cDCs) from hematopoietic stem cells. However, the function of PU.1 in mature cDC remains unclear. To test the possible role of PU.1 in mature cDCs, we developed mice lacking PU.1 selectively in mature cDCs (DC-PU.1D/D mice) by crossing a PU.1flox mouse line with a transgenic Itgax (CD11c)-Cre strain. In these mice, cDCs were dramatically reduced in spleen, thymus, lymph node, and skin, down to <40%, <25%, <10% and <5% of DCs in control mice respectively, whereas bone marrow cDCs and common dendritic cells progenitors (CDPs) were not affected. Surprisingly, T cell numbers were significantly decreased in DC-PU.1D/D mice, whereas thymic T cell development was normal, suggesting that maintenance of mature T cell pool might be impaired, presumably by dysfunction of PU.1D/D cDCs. In fact, PU.1D/D cDCs failed to efficiently induce ovalbumin-specific T cell response and to produce inflammatory cytokines in response to Toll like receptor (TLR) stimulation both in vitro and in vivo. The intravenous transfer of spleen PU.1D/D cDCs failed to repopulate the spleen of recipient mice, suggesting their poor survival in vivo. Furthermore, the expression of critical molecules for inflammatory responses was downregulated in PU.1D/D cDCs as compared to normal cDCs. These molecules included Myd88 and NFkB that are downstream molecules of TLR signaling, CD86 that is required for T cell stimulation, and CCR7 that is required for cDC migration. These results clearly show that PU.1 is required for development of the functional cDC pool, and the cDC pool plays a critical role in T cell homeostasis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The lymphoproliferative defect in CTLA-4–deficient mice is ameliorated by an inhibitory NK cell receptor

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4509-4516 ◽  
Author(s):  
Cynthia A. Chambers ◽  
Joonsoo Kang ◽  
Yongjian Wu ◽  
Werner Held ◽  
David H. Raulet ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Cell Responses ◽  
Deficient Mice

T-cell responses are regulated by activating and inhibiting signals. CD28 and its homologue, cytotoxic T-lymphocyte antigen 4 (CTLA-4), are the primary regulatory molecules that enhance or inhibit T-cell activation, respectively. Recently it has been shown that inhibitory natural killer (NK) cell receptors (NKRs) are expressed on subsets of T cells. It has been proposed that these receptors may also play an important role in regulating T-cell responses. However, the extent to which the NKRs modulate peripheral T-cell homeostasis and activation in vivo remains unclear. In this report we show that NK cell inhibitory receptor Ly49A engagement on T cells dramatically limits T-cell activation and the resultant lymphoproliferative disorder that occurs in CTLA-4–deficient mice. Prevention of activation and expansion of the potentially autoreactive CTLA-4−/− T cells by the Ly49A-mediated inhibitory signal demonstrates that NKR expression can play an important regulatory role in T-cell homeostasis in vivo. These results demonstrate the importance of inhibitory signals in T-cell homeostasis and suggest the common biochemical basis of inhibitory signaling pathways in T lymphocytes.

scholarly journals Autophagy-independent functions of UVRAG are essential for peripheral naive T-cell homeostasis

2015 ◽  
Vol 112 (4) ◽  
pp. 1119-1124 ◽  
Author(s):  
Samia Afzal ◽  
Zhenyue Hao ◽  
Momoe Itsumi ◽  
Yasser Abouelkheer ◽  
Dirk Brenner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Knockout ◽  
Homozygous Deletion ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Independent Functions ◽  
Naïve T Cell ◽  
Naive T Cell

UV radiation resistance-associated gene (UVRAG) encodes a tumor suppressor with putative roles in autophagy, endocytic trafficking, and DNA damage repair but its in vivo role in T cells is unknown. Because conditional homozygous deletion of Uvrag in mice results in early embryonic lethality, we generated T-cell–specific UVRAG-deficient mice that lacked UVRAG expression specifically in T cells. This loss of UVRAG led to defects in peripheral homeostasis that could not be explained by the increased sensitivity to cell death and impaired proliferation observed for other autophagy-related gene knockout mice. Instead, UVRAG-deficient T-cells exhibited normal mitochondrial clearance and activation-induced autophagy, suggesting that UVRAG has an autophagy-independent role that is critical for peripheral naive T-cell homeostatic proliferation. In vivo, T-cell–specific loss of UVRAG dampened CD8+ T-cell responses to LCMV infection in mice, delayed viral clearance, and impaired memory T-cell generation. Our data provide novel insights into the control of autophagy in T cells and identify UVRAG as a new regulator of naïve peripheral T-cell homeostasis.

scholarly journals An In Vivo IL-7 Requirement for Peripheral Foxp3+ Regulatory T Cell Homeostasis

2012 ◽  
Vol 188 (12) ◽  
pp. 5859-5866 ◽  
Author(s):  
Grace Y. Kim ◽  
Davinna L. Ligons ◽  
Changwan Hong ◽  
Megan A. Luckey ◽  
Hilary R. Keller ◽  
...  
Keyword(s):  
T Cell ◽  
Regulatory T Cell ◽  
T Cell Homeostasis ◽  
Cell Homeostasis

scholarly journals NAD+Released during Inflammation Participates in T Cell Homeostasis by Inducing ART2-Mediated Death of Naive T Cells In Vivo

2007 ◽  
Vol 179 (1) ◽  
pp. 186-194 ◽  
Author(s):  
Sahil Adriouch ◽  
Sandra Hubert ◽  
Severine Pechberty ◽  
Friedrich Koch-Nolte ◽  
Friedrich Haag ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Naive T Cells ◽  
Naïve T Cells

scholarly journals The transcriptional cofactor IRF2BP2 plays a key role in T cell homeostasis and Treg cell expansion

2021 ◽  
Author(s):  
Giuliana P. Mognol ◽  
Barbara Oliveira-Vieira ◽  
Natalia Pinheiro-Rosa ◽  
Barbara C. Peixoto ◽  
Marianna Boroni ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
T Cell Proliferation ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Cell Responses

The levels of the co-transcriptional regulator IRF2BP2 (Interferon Regulatory Factor-2 Binding Protein-2) decrease with T cell activation and, when ectopically expressed, it reduces T cell proliferation. To further characterize the function of IRF2BP2 in T cell responses in vivo, we generated a conditional transgenic knock-in mouse that overexpresses IRF2BP2 in T lymphocytes. Overexpression of IRF2BP2 leads to a reduction in the T cell compartment of naive animals, upregulation of Foxp3 and Ifng; an increase in the frequency of regulatory T cells (Tregs), a preferential Th1 differentiation with increase of IFN-γ production and a reduction of T cell proliferation, suggesting a disruption in T cell homeostasis. Interestingly, knock-in mice displayed reduced clinical and inflammatory signs of Experimental Autoimmune Encephalomyelitis (EAE) when compared to the control mice, with an augmented frequency of Treg cells. Altogether, our findings indicate that IRF2BP2 might help to control exacerbated T cell responses and point to a role for IRF2BP2 in preventing T cell autoimmunity.

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