Mapping the SLP76 interactome in T cells lacking each of the GRB2-family adaptors reveals molecular plasticity of the TCR signaling pathway

Ruminski, Kilian; Celis-Gutierrez, Javier; Jarmuzynski, Nicolas; Maturin, Emilie; Audebert, Stéphane; Camoin, Luc; Voisinne, Guillaume; Malissen, Bernard; Roncagalli, Romain

doi:10.3389/fimmu.2023.1139123

Cited by 2 publications

(3 citation statements)

References 51 publications

(72 reference statements)

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“…Thus, TCR-induced recruitment of SLP-76 to LAT is profoundly reduced in the absence of Gads, but is not affected by deletion of other Grb2-family members (32,48).…”

Section: Discussionmentioning

confidence: 94%

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Survival and Developmental Progression of Unselected Thymocytes in the Absence of the T Cell Adaptor Gads

Shalah

Hallumi

Klopstock

et al. 2023

Preprint

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Gads is an immune adaptor that bridges the TCR-inducible interaction of two additional adaptors: SLP-76 and LAT. Thymic development is profoundly impaired in the absence of SLP-76 or LAT, but moderately impaired in Gads-deficient mice, which accumulate non-naïve (CD44+) peripheral T cells. To better distinguish Gads-dependent and -independent developmental transitions, we performed tamoxifen-induced ablation of Gads (GadsiKO), accompanied by the expression of tdTomato, and compared the co-development of Gads-expressing (Tom-) and -ablated (Tom+) thymocytes within the same mouse. The frequency of GadsiKO (Tom+) thymocytes decreased at Gads-dependent junctures but remained high in Gads-independent lineages. Within the DN compartment, Gads was required for conventional β-selection, but not for the γδ or NKT lineages. GadsiKO DP thymocytes were overwhelmingly CD5-, indicating impaired self peptide-MHC responsiveness; yet exhibited reduced death by neglect. Instead, an aberrant population of CD5- GadsiKO thymocytes progressed as far as the CD4 SP compartment, while lacking key characteristics of positively selected thymocytes. Distinct, CD5+ GadsiKO SP populations were positively-selected and TCR responsive, suggesting that they include one or more Gads-independent developmental lineages. In particular, the development of innate-like NKT cells, CD44+ PLZF+ CD4+ cells, and CD44+ Eomes+ CD8+ cells was favored in the absence of Gads. Our results suggest that Gads regulates thymic development, by promoting conventional αβ T cell development and death by neglect, while suppressing innate-like thymic developmental fates.

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“…Thus, TCR-induced recruitment of SLP-76 to LAT is profoundly reduced in the absence of Gads, but is not affected by deletion of other Grb2-family members (32,48).…”

Section: Discussionmentioning

confidence: 94%

“…Grb2 most likely cannot compensate for Gads, since its binding to SLP-76 occurs at 1000-fold lower affinity [29]. Thus, TCR-induced recruitment of SLP-76 to LAT is profoundly reduced in the absence of Gads, but is not affected by deletion of other Grb2-family members [36,52].…”

Section: Discussionmentioning

confidence: 99%

Survival and Developmental Progression of Unselected Thymocytes in the Absence of the T Cell Adaptor Gads

Shalah

Hallumi

Klopstock

et al. 2023

Preprint

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“…However, in the periphery these mice have reduced a percentage of CD8 + T cells and increased gdT cells. Additionally, Ruminski et al (6), using CRISPR gene editing and affinity purification coupled with mass spectrometry, have revealed the important role of GRB2 family adaptors in TCR signaling plasticity relating to the SLP-76 interactome.…”

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confidence: 99%

Editorial: Community series in adaptor molecules in T cell signaling, volume II

2023

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T cells are the essential effectors of the adaptive immunity. They use their unique receptor, the T cell receptor (TCR), to specifically recognize and respond to antigens associated with the major histocompatibility complex (MHC) molecules. Signal transduction of the TCR is initiated with the function of the CD3 subunits of the TCR complex. The very first event in TCR/CD3 complex activation is the phosphorylation of the cytoplasmic tails of CD3z by the tyrosine kinase Lck, allowing the recruitment of the kinase ZAP70 to phosphorylate a number of downstream mediators and effectors to amplify TCR/CD3 signaling.Adaptor molecules couple the TCR/CD3 complex to a variety of signaling molecules involved in T cell activation and as such play a key role as signal amplifiers. Adaptors include both transmembrane and cytosolic molecules, such as LAT, SLP-76, GRB2, SHC, and Gads. While some adaptor molecules, like TSAd and Nck, may participate in proximal TCR/CD3 signaling by recruiting Lck, other adaptors, such as PAG and SIT, may negatively regulate TCR signaling, thereby contributing to signal termination. Signaling by the TCR has been heavily investigated for exploitation in cancer immunotherapy through approaches involving CAR T cells or other engineered T cells. Adaptor proteins have fundamental roles in the finetuning the tightly controlled intricate process of TCR/CD3 signaling both in T cell homeostasis and immune responses. Harnessing their signal modulating properties may help develop better cancer immunotherapies. Additionally, adaptor molecules are among the components of the TCR signaling cascade being investigated for their implication in pathological conditions including autoimmunity and hematologic malignancies, and some adaptor molecules have been identified as therapeutic targets to treat or alleviate those conditions. This Research Topic focuses on adaptor proteins that participate in T cell signaling and thus modulate the adaptive immune response.Luff et al. ( 1) have documented the indispensable role of phosphoinositide 3-kinase d (PI3Kd) that is recruited to and activated at the TCR signalosome. Using mass spectrometry, biochemical approaches and CRIPR gene editing, they demonstrated that PI3Kd interacts with many adaptor proteins involved in naïve T cell activation and proliferation. Importantly, these novel interactions between PI3Kd and adaptor proteins occurring in T cells may be Frontiers in Immunology frontiersin.org 01

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Mapping the SLP76 interactome in T cells lacking each of the GRB2-family adaptors reveals molecular plasticity of the TCR signaling pathway

Cited by 2 publications

References 51 publications

Survival and Developmental Progression of Unselected Thymocytes in the Absence of the T Cell Adaptor Gads

Survival and Developmental Progression of Unselected Thymocytes in the Absence of the T Cell Adaptor Gads

Editorial: Community series in adaptor molecules in T cell signaling, volume II

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