The Transmembrane Adapter Protein SIT Regulates Thymic Development and Peripheral T-Cell Functions

Simeoni, Luca; Posevitz, Vilmos; Kölsch, Uwe; Meinert, Ines; Bruyns, Eddy; Pfeffer, Klaus; Reinhold, Dirk; Schraven, Burkhart

doi:10.1128/mcb.25.17.7557-7568.2005

Cited by 31 publications

(66 citation statements)

References 55 publications

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“…CD8 ϩ T cells were either left untreated or stimulated with CD3/CD8 mAbs or OT-I-streptamers, lysed as described in (13) and protein concentration was determined using the Roti-Nanoquant reagent (Roth) according to manufacturer's instruction. The samples were analyzed by Western blotting.…”

Section: Western Blotting and Immunoprecipitationmentioning

confidence: 99%

Dynamics of Proximal Signaling Events after TCR/CD8-Mediated Induction of Proliferation or Apoptosis in Mature CD8+ T Cells

Wang¹,

Simeoni²,

Lindquist³

et al. 2008

The Journal of Immunology

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Engagement of the TCR can induce different functional outcomes such as activation, proliferation, survival, or apoptosis. How the TCR-mediated signaling cascades generating these distinct cellular responses are organized on the molecular level is so far not completely understood. To obtain insight into this question, we analyzed TCR/CD8-mediated signaling events in mature OT-I TCR transgenic T cells under conditions of stimulation that lead to either proliferation or apoptosis. These experiments revealed major differences in the phosphorylation dynamics of LAT, ZAP70, protein kinase B, phospholipase C-γ1, protein kinase D1, and ERK1/2. Moreover, input signals leading to apoptosis induced a strong, but transient activation of ERK1/2 mainly at sites of TCR-engagement. In contrast, stimuli promoting survival/proliferation generated a low and sustained activation of ERK1/2, which colocalizes with Ras in recycling endosomal vesicles. The transient activation of ERK1/2 under pro-apoptotic conditions of stimulation is at least partially due to the rapid polyubiquitination and subsequent degradation of ZAP70, whereas the sustained activation of ERK1/2 under survival promoting conditions is paralleled by the induction/phosphorylation of anti-apoptotic molecules such as protein kinase B and Bcl-xL. Collectively, our data provide signaling signatures that are associated with proliferation or apoptosis of T cells.

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Section: Western Blotting and Immunoprecipitationmentioning

confidence: 99%

Dynamics of Proximal Signaling Events after TCR/CD8-Mediated Induction of Proliferation or Apoptosis in Mature CD8+ T Cells

Wang¹,

Simeoni²,

Lindquist³

et al. 2008

The Journal of Immunology

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“…Moreover, we have shown that SIT Ϫ/Ϫ mice displayed an enhanced positive selection in the thymus, hyperactivated peripheral T cells, and an increased homeostatic proliferation [7][8][9]. Conversely, mice lacking TRIM [10], PAG [11,12], and LIME [13] have no significant alteration of the immune system.…”

Section: Introductionmentioning

confidence: 89%

“…Recently, it has been shown that SIT and LAX are negative regulators of lymphocyte activation [5,7,9]. However, as SIT Ϫ/Ϫ and LAX Ϫ/Ϫ mice display only mild alterations in immune functions, we investigated whether the loss of SIT and LAX would result in a more severe phenotype than the single KOs.…”

Section: Accumulation Of Activated Cd4 ؉ T Cells In Dko Micementioning

confidence: 99%

“…SIT Ϫ/Ϫ and LAX Ϫ/Ϫ mice were described previously [5,7]. LAX Ϫ/Ϫ mice were kindly provided by W. Zhang.…”

Section: Micementioning

confidence: 99%

“…SIT Ϫ/Ϫ mice were mated with LAX Ϫ/Ϫ to generate SIT ϩ/Ϫ LAX ϩ/Ϫ mice, which were then crossed to generate SIT Ϫ/Ϫ LAX Ϫ/Ϫ double-deficient (DKO) mice. Mice were genotyped for SIT and LAX mutations as described previously [5,7]. The mice used in this study were between 3 and 12 month of age, as indicated.…”

Section: Micementioning

confidence: 99%

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Cooperative immunoregulatory function of the transmembrane adaptor proteins SIT and LAX

Arndt

Kalinski

Reinhold

et al. 2013

Journal of Leukocyte Biology

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Lymphocyte activation is crucial for the generation of immune responses. In vitro studies have demonstrated that TRAPs are critical regulators of lymphocyte activation. However, more recent in vivo studies have demonstrated that with the exception of LAT, TRAPs, such as SIT, NTAL, and LAX, only minimally affect immune cell functions. Additional studies have suggested that the mild or the apparent lack of a phenotype displayed by most TRAP KO mice may be explained by functional redundancy among this family of adaptors. In fact, it has been shown that the phenotype of NTAL/LAT or SIT/TRIM double-deficient mice is more severe than that of the single KOs. Here, we have evaluated whether SIT and the related transmembrane adaptor LAX have overlapping functions by generating SIT/LAX DKO mice. We show that DKO, in contrast to single KO mice, accumulate large numbers of activated CD4 ϩ T cells in the spleen. Moreover, conventional B cells from DKO mice are hyperproliferative upon CD40 stimulation. Additionally, we found that DKO mice displayed an expansion of the B1 cell pool in the peritoneal cavity, hypergammaglobulinaemia, and an enhanced immune response to the T1-independent antigen, TNP-LPS. Finally, we demonstrate that SIT/LAX double deficiency resulted in a more pronounced breakdown of peripheral tolerance and the development of autoimmunity characterized by ANAs and renal disease (glomerulonephritis and proteinuria). Collectively, our data indicate that SIT and LAX are important negative regulators of immune responses that functionally cooperate.

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Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19

Cordero

Milne

et al. 2021

Hum Genet

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The Transmembrane Adapter Protein SIT Regulates Thymic Development and Peripheral T-Cell Functions

Abstract: SIT is a transmembrane adapter protein that modulates signals emanating from the T-cell receptor (TCR

Cited by 31 publications

References 55 publications

Dynamics of Proximal Signaling Events after TCR/CD8-Mediated Induction of Proliferation or Apoptosis in Mature CD8+ T Cells

Dynamics of Proximal Signaling Events after TCR/CD8-Mediated Induction of Proliferation or Apoptosis in Mature CD8+ T Cells

Cooperative immunoregulatory function of the transmembrane adaptor proteins SIT and LAX

Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19

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