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

COPYRIGHT © 2023 Pongcharoen, Spurkland and Baldari. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Editorial PUBLISHED 26 July 2023 DOI 10.3389/fimmu.2023.1243039

applied to control the threshold of activation and diversify the inputs for PI3K signaling in effector T cells. Gartshteyn et al. (2) have reviewed the function of the signaling lymphocyte activation molecules (SLAM), a family of T cell transmembrane co-receptors that modulate T cell response to antigens. SLAM signal via interaction with the adaptor protein SH2D1A or SLAM associated protein (SAP). The latter functions to recruit tyrosine kinases and shield phosphorylated sites from dephosphorylation. They suggested that a balanced SLAM-SAP signaling in T cells is required for healthy immunity and that alteration of this pathway could be associated with autoimmune disorders. Hence, SLAM-SAP signaling could be a promising treatment target for autoimmunity.
Lo and Weiss (3) have revisited to the critical role of the linker for activation of T cells (LAT) in T cell receptor ligand discrimination. Selfand non-self ligand discrimination has been believed to be a core principle underlying T cell-mediated immunity. The authors discussed new evidence that supports the kinetic proofreading model of TCR ligand discrimination that is important for the outcome of TCR signaling. The role of LAT and the SH2 domain-containing leukocyte protein of 76 KDa (SLP-76) in thymocyte development and activation of mature T cells is reviewed by Dinur-Schejter et al. (4) Besides clear evidence from several murine models, the defects in LAT also cause human inborn errors of immunity. Similarly, the function of SLP-76 has been shown to be essential in T cell lines, mouse models and a human infant reported with autoimmune and lymphoproliferative manifestation. Thus, these two adaptor molecules are important for normal immunity. In addition, the role of LAT as a possible checkpoint for T cell development and activation has been demonstrated by Arbulo-Echevaria et al. (5) They showed that mice expressing mutant LAT (glycine to aspartic acid at position 135) have an increase in the percentage of CD4 + CD8 + double-positive but a decrease in that of CD4 + and CD8 + single-positive thymocytes. 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.
Borroto et al. (7) have extended these essential role of the proline-rich sequence in CD3e that binds to Nck adaptor protein in the differentiation and function of pro-inflammatory Thgd17 cells implicated in an imiquimod model of skin inflammation. This mouse model resembles psoriasis in humans, hence suggesting the novel approach for the treatment of this disease.
The adhesion and degranulation-promoting adaptor protein (ADAP) and the Src kinase associated protein 1 and 2 (SKAP1 and SKAP2) have been reviewed by Dadwal et al. (8) for their important and multiple roles in TCR/CD3 signalosome and signal transduction in T cells. The authors have pointed out the crucial roles of these molecules relating to the function of leucocyte function associated antigen 1 (LFA-1), LAT and SLP-76. In mice, defects in ADAP translate into inflammatory processes leading to demyelination and axonal damage. The authors suggested further investigation on T cells with ADAP mutations in humans with small-platelet thrombocytopenia and increased bleeding tendency. In their review, Liu et al. (9), expanded on this topic and explained how SKAP1 regulates the activation of integrin and optimizes the cell cycling of proliferating T cells through multiple interactions with various mediators.
Velnati et al. (10) have reported a novel signaling pathway mediated by binding of Wiskott-Aldrich syndrome protein (WASp) and diacylglycerol kinase alpha (DGKa). Efficient TCR signaling is known to require inhibition of DGKa triggered in response to SAP activation. The authors showed that non-catalytic region of tyrosine kinase-1 (Nck-1) and the small G protein CDC42 connect the interaction of WASp and DGKa leading to the inhibition of DGKa activity and T cell IL-2 response.
Signaling transduction in T cells eventually leads to the NF-kB transcription factor activation. This process is a critical step for T cell survival, proliferation, differentiation and function. O'Neill et al. have demonstrated the existence of a signalosome containing three interacting proteins, caspase recruitment domain family member 11 (CARD11), B-cell lymphoma/leukemia 10 (BCL10), and mucosaassociated lymphoid tissue 1 (MALT1), called the CBM complex. MALT1 is known to be a scaffold for the E3 ligase tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6). The authors showed in a mouse model that the CMB is crucial for balancing T cell activation and homeostasis. In addition, Oikawa et al. (11) have added the new finding that this CBM complex is ubiquitinated by the E3 ubiquitin ligase called LUBAC. Using Jurkat cells in various assays and mathematical simulation, they demonstrated that LUBAC controls the activation of NF-kB, critically mediating T cell functions. In addition, Hornick and Bishop have reviewed the role of TRAF3 as a mediator of T cell differentiation and effector function. The essential function of TRAF3 has been demonstrated both in murine models and human disease caused by germline TRAF3 deficiency. The affected patients have autoimmunity, immunodeficiency, and a predisposition to B cell malignancies.
Collectively, this Research Topic contributes to provide new insights into T cell biology area involving adaptor proteins, including proximal and distal TCR signaling, thymocyte development and T cell differentiation, signalosomes relating to T cell signal transduction and regulation of cytokines and other signaling mediators. The knowledge obtained can set the foundation to novel approaches for treatment of autoimmunity and cancer.
Author contributions SP, AS, and CB drafted and edited the present editorial. All authors contributed to the article and approved the submitted version.

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