Activation of T lymphocytes constitutes a central event in adaptive immune responses against infectious pathogens or tumor cells. Antigen recognition by T cells is performed through the T cell receptor (TCR) which triggers a cascade of intracellular signals leading to T cell activation and development of effector functions. Proper TCR signaling requires the sequential activities of lymphocyte-specific protein tyrosine kinase (Lck) and zeta-chain-associated protein kinase 70 (ZAP-70) kinases, resulting in the phosphorylation of tyrosine residues located in the CD3 immunoreceptor tyrosine-based activation motifs (ITAMs) and the linker for activation of T cells (LAT) adaptor, respectively. Phosphorylation of LAT causes the recruitment of many proteins to the membrane, allowing their phosphorylation and activation of downstream signaling pathways. Although there has been a huge increase in knowledge on early intracellular signaling in recent years, much less is known about the molecular mechanisms negatively regulating early TCR intracellular signals.
Recent reports have revealed the role of some key players in the negative regulation of early TCR associated intracellular signals. Lck and ZAP-70 tyrosine kinases, the CD45 phosphatase, the transmembrane adaptors LAT and NTAL and other molecules can play an activatory role in intracellular signaling; however they are also able to behave as negative regulators of T cells, unveiling their involvement in intrinsic negative feedback loops. This has consequences in the way T cells discriminate foreign from self-antigens, how naive T cells are activated and differentiate into effector and memory cells, and also in immune homeostasis. All these events are of critical relevance for T cell development and efficient immune responses, allowing the avoidance of autoimmune disorders. A deeper understanding of how the TCR signaling cassette is self-regulated is necessary, not only for the benefit of Cell Biology and Immunology but also to lay the foundations for future advances in therapies for immune-based diseases.
The aim of the current Research Topic is to collect recent and novel research trends in field of early intracellular signaling coupled to the TCR/CD3 complex. Areas to be covered in this Research Topic may include, but are not limited to:
• Role of tyrosine and threonine/serine kinases phosphatases as regulators of TCR signaling.
• Rapid endocytic recycling of TCR and associated signaling adaptors as a regulatory hub in TCR signaling.
• Costimulatory and coinhibitory receptors in early intracellular signaling coupled to the TCR/CD3 signaling
cassette.
• Relevance of negative regulation of the TCR signaling cassette for thymic maturation: TCR signaling during
thymic positive and negative selection.
• Perturbations of regulatory mechanisms of TCR signaling and pathological implications, including new
therapeutic approaches for immune based pathologies.
• Bioenergetics of T cell activation.
• Differences in TCR signaling pathways between effector and regulatory T cells.
• Membrane dynamics and nanoscale organization of TCR associated molecules in the regulation of TCR
signaling.
We welcome authors to submit Original Research, Review and Case Reports focusing on the regulatory mechanisms of early intracellular signaling in T lymphocytes.
Activation of T lymphocytes constitutes a central event in adaptive immune responses against infectious pathogens or tumor cells. Antigen recognition by T cells is performed through the T cell receptor (TCR) which triggers a cascade of intracellular signals leading to T cell activation and development of effector functions. Proper TCR signaling requires the sequential activities of lymphocyte-specific protein tyrosine kinase (Lck) and zeta-chain-associated protein kinase 70 (ZAP-70) kinases, resulting in the phosphorylation of tyrosine residues located in the CD3 immunoreceptor tyrosine-based activation motifs (ITAMs) and the linker for activation of T cells (LAT) adaptor, respectively. Phosphorylation of LAT causes the recruitment of many proteins to the membrane, allowing their phosphorylation and activation of downstream signaling pathways. Although there has been a huge increase in knowledge on early intracellular signaling in recent years, much less is known about the molecular mechanisms negatively regulating early TCR intracellular signals.
Recent reports have revealed the role of some key players in the negative regulation of early TCR associated intracellular signals. Lck and ZAP-70 tyrosine kinases, the CD45 phosphatase, the transmembrane adaptors LAT and NTAL and other molecules can play an activatory role in intracellular signaling; however they are also able to behave as negative regulators of T cells, unveiling their involvement in intrinsic negative feedback loops. This has consequences in the way T cells discriminate foreign from self-antigens, how naive T cells are activated and differentiate into effector and memory cells, and also in immune homeostasis. All these events are of critical relevance for T cell development and efficient immune responses, allowing the avoidance of autoimmune disorders. A deeper understanding of how the TCR signaling cassette is self-regulated is necessary, not only for the benefit of Cell Biology and Immunology but also to lay the foundations for future advances in therapies for immune-based diseases.
The aim of the current Research Topic is to collect recent and novel research trends in field of early intracellular signaling coupled to the TCR/CD3 complex. Areas to be covered in this Research Topic may include, but are not limited to:
• Role of tyrosine and threonine/serine kinases phosphatases as regulators of TCR signaling.
• Rapid endocytic recycling of TCR and associated signaling adaptors as a regulatory hub in TCR signaling.
• Costimulatory and coinhibitory receptors in early intracellular signaling coupled to the TCR/CD3 signaling
cassette.
• Relevance of negative regulation of the TCR signaling cassette for thymic maturation: TCR signaling during
thymic positive and negative selection.
• Perturbations of regulatory mechanisms of TCR signaling and pathological implications, including new
therapeutic approaches for immune based pathologies.
• Bioenergetics of T cell activation.
• Differences in TCR signaling pathways between effector and regulatory T cells.
• Membrane dynamics and nanoscale organization of TCR associated molecules in the regulation of TCR
signaling.
We welcome authors to submit Original Research, Review and Case Reports focusing on the regulatory mechanisms of early intracellular signaling in T lymphocytes.
