Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling

Wang, Di; Zheng, Mingzhu; Lei, Lei; Ji, Jian; Yao, Yunliang; Qiu, Yuanjun; Ma, Lie; Lou, Jun; Ouyang, Chuan; Zhang, Xue; He, Yaoyao; Chen, Jun; Wang, Lie; Kuang, Ying; Wang, Jianli; Cao, Xuetao; Lu, Linrong

doi:10.1038/ni.2301

Cited by 71 publications

(81 citation statements)

References 33 publications

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“…DN3 transition to DN4 and DP stage requires successful TCRβ gene rearrangements, namely V(D)J recombination, and β-selection (1–4). We found that Vβ11-Jβ2 and Vβ5-Jβ2 recombination was moderately impaired upon RhoA deletion, whereas Vβ8-Jβ2, Dβ2-Jβ2, Dβ2.1-Jβ2.7, and Dβ1.1-Jβ1.7 rearrangements were completely intact (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Gene Targeting RhoA Reveals Its Essential Role in Coordinating Mitochondrial Function and Thymocyte Development

Zhang

Konstantinidis

Yang

et al. 2014

The Journal of Immunology

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Thymocyte development is regulated by complex signaling pathways. How these signaling cascades are coordinated remains elusive. RhoA of the Rho family small GTPases plays an important role in actin cytoskeleton organization, cell adhesion, migration, proliferation, and survival. Nonetheless, the physiological function of RhoA in thymocyte development is not clear. By characterizing a conditional gene targeting mouse model bearing T cell deletion of RhoA, we show that RhoA critically regulates thymocyte development by coordinating multiple developmental events. RhoA gene disruption caused a strong developmental block at the pre-TCR checkpoint and during positive selection. Ablation of RhoA led to reduced DNA synthesis in CD4−CD8−, CD4+CD8−, and CD4−CD8+ thymocytes but not in CD4+CD8+ thymocytes. Instead, RhoA-deficient CD4+CD8+ thymocytes showed an impaired mitosis. Furthermore, we found that abrogation of RhoA led to an increased apoptosis in all thymocyte subpopulations. Importantly, we show that the increased apoptosis was resulted from reduced pre-TCR expression and increased production of reactive oxygen species (ROS) which may be due to an enhanced mitochondrial function, as manifested by increased oxidative phosphorylation, glycolysis, mitochondrial membrane potential, and mitochondrial biogenesis in RhoA-deficient thymocytes. Restoration of pre-TCR expression or treatment of RhoA-deficient mice with a ROS scavenger NAC partially restored thymocyte development. These results suggest that RhoA is required for thymocyte development and indicate for the first time that fine-tuning of ROS production by RhoA, through a delicate control of metabolic circuit, may contribute to thymopoiesis.

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Section: Resultsmentioning

confidence: 99%

“…T cell development in thymus proceeds through a series of differentiation stages (1–4). The most immature populations in thymus comprise CD4 − CD8 − double-negative (DN) thymocytes.…”

Section: Introductionmentioning

confidence: 99%

Gene Targeting RhoA Reveals Its Essential Role in Coordinating Mitochondrial Function and Thymocyte Development

Zhang

Konstantinidis

Yang

et al. 2014

The Journal of Immunology

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“…However, recent investigations have indicated that more non-MHC genes may be associated with RA susceptibility, such as PTPN22, PADI4, TRAF1-C5, STAT4, and ARL15 [20][21][22][23][24][25][26][27]. In our previous work, we identified Tespa1 [7], a gene that interacted with the linker for activation of T cells (LAT) signalosome formed during TCR signaling, thus playing a key role in the regulation of T cell development. Liu et al's work indicated that the Tespa1 gene is not involved in the genetic predisposition to ankylosing spondylitis (AS) but may play an important role in the clinical characteristics of AS [11].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous work demonstrated that a gene associated with immune responses, Tespa1, is a component of the T cell receptor (TCR) signalosome and is essential for T cell selection and maturation through the regulation of TCR signaling during T cell development [7]. Tespa1 also negatively regulates FcεRI-mediated signaling and the mast cell-mediated allergic response [8].…”

Section: Introductionmentioning

confidence: 99%

Tespa1 is associated with susceptibility but not severity of rheumatoid arthritis in the Zhejiang Han population in China

et al. 2015

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Observational and experimental studies in animal models have shown that Tespa1 may be associated with B cell function and the onset of rheumatoid arthritis (RA). We hypothesized that Tespa1 may also play an important role in patients with RA. To test this hypothesis, we investigated the expression level, gene polymorphisms, and promoter methylation of the Tespa1 gene in 77 RA patients and 113 matched healthy controls. We found that the expression of Tespa1 is significantly lower in RA patients with both low and moderate-to-high disease activity. Moreover, patients with familial (first-degree siblings) but not sporadic RA have a statistically significant difference at the rs4758993 locus with healthy people. Furthermore, we found seven methylation sites on the Tespa1 promoter, but no evidence of the association between methylation at these sites and RA susceptibility. These data support a potential role for Tespa1 in the pathogenesis of RA.

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“…Indeed, studies with mice lacking TCR structural components (34,35) or downstream signaling molecules such as LCK (30), LAT (39), GRB2 (40), TESPA1 (41), and ITK (42) show severe defects in T cell development with significant immunodeficiency (reviewed in reference 43). LCK acts immediately downstream of the TCR, and upon its activation, it phosphorylates THEMIS (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

THEMIS Is Required for Pathogenesis of Cerebral Malaria and Protection against Pulmonary Tuberculosis

et al. 2015

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We identify an N-ethyl-N-nitrosourea (ENU)-induced I23N mutation in the THEMIS protein that causes protection against experimental cerebral malaria (ECM) caused by infection with) and chemokines (IL-8, monocyte chemoattractant protein 1, and KC), elimination of the microbial threat, and tissue destruction and repair (1, 2). In the presence of persistent tissue injury or of an unusual infectious or environmental insult, overexpression of proinflammatory mediators or insufficient production of antiinflammatory signals (prostaglandin E2, IL-10, TGF-␤, and IL1Ra) causes acute or chronic states of pathological inflammation. Population studies of chronic inflammatory diseases such as inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and others have identified a complex genetic architecture of disease susceptibility, with additional effects of microbial triggers that initiate and sustain pathological inflammation (3-5). Many of the mapped disease loci and genes are common to two or more such diseases, suggesting that some critical features of pathogenesis are shared by these conditions. Cerebral malaria (CM) is an acute, life-threatening encephalitis that is a complication of Plasmodium falciparum infection in children and pregnant women (6). CM-associated neuroinflammation has been studied in a mouse model of experimental CM (ECM) induced by infection with Plasmodium berghei ANKA (7). In this model, brain endothelial cells activated by trapped parasitized red blood cells (pRBCs) produce cytokines and chemotactic factors that recruit neutrophils and activated CD8 ϩ and CD4 ϩ T cells. Release of cytotoxic molecules by inflammatory leukocytes leads to loss of integrity of the blood-brain barrier (BBB), microthrombosis, and hypoxia of the brain parenchyma, leading to neurological symptoms, including seizures and coma, and ultimately death (8,9). Recent findings show that elevated levels of inflammatory molecules (TNF-␣, IFN-␥, IL-1␤, macrophage inflammatory protein 1␣ [MIP-1␣], MIP-1␤, CXCL10, and complement component 5a [C5a]) are associated with an increased risk of CM, supporting a neuroinflammatory component of human CM (10-12). Antibody-mediated cell ablation experiments have demonstrated a strong pathological role for CD8 ϩ and CD4 ϩ T cells, NK cells, and neutrophils in ECM (7). Conversely, we and others have demonstrated an ECM-protective effect of mutations in major proinflammatory genes such as those for IFN-␥ (Ifng) and its receptor (Ifngr1), lymphotoxin (Lta/Ltb), complement component 5a (Hc) (reviewed in reference 13), and certain transcription factors that regulate the expression of these genes in myeloid and lymphoid cells, including IFN regulatory factor 1 (IRF1) (14), IRF8, and STAT1 (15). Whole-brain transcript profiling along with chromatin immunoprecipitation and sequencing data comparing ECM-susceptible and -resistant (Irf8 myls BXH2 strain) mice identified a core transcriptome activated during ECM (15). This transcriptome contains several genes, including those for IRF1, IRF8, and...

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Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling

Cited by 71 publications

References 33 publications

Gene Targeting RhoA Reveals Its Essential Role in Coordinating Mitochondrial Function and Thymocyte Development

Gene Targeting RhoA Reveals Its Essential Role in Coordinating Mitochondrial Function and Thymocyte Development

Tespa1 is associated with susceptibility but not severity of rheumatoid arthritis in the Zhejiang Han population in China

THEMIS Is Required for Pathogenesis of Cerebral Malaria and Protection against Pulmonary Tuberculosis

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