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2025BIOMED010.pdf
Doctoral thesis

FCRL3 is an immunomodulatory receptor that restrains the activation of human memory T lymphocytes

  • 2025

PhD: Università della Svizzera italiana

T lymphocytes
Immune regulation
FCRL3
T cell activation
Cytotoxic T cells
Autoimmunity
Immunomodulation
Inhibitory receptors
Gene regulation
English T lymphocytes are central mediators of adaptive immunity, orchestrating responses that ensure the targeted elimination of pathogens. CD4⁺ T lymphocytes primarily function through the secretion of cytokines, which coordinate the activity of other immune cells, whereas CD8⁺ T lymphocytes directly eliminate infected or malignant cells. The initiation of an effective immune response requires accurate antigen recognition, followed by tightly regulated gene expression programs that drive a robust yet controlled immune activation. Such regulation ensures the efficient clearance of infected cells while enabling restoration of immune homeostasis once the pathogen has been eliminated. Failure of these regulatory mechanisms can result in sustained or excessive T cell activity, leading to pathological outcomes such as chronic inflammation and autoimmunity. The family of Fc receptor–like (FCRL) proteins exhibits immunomodulatory functions. The presence of immunoreceptor tyrosine-based activation motifs (ITAMs) and inhibitory motifs (ITIMs) within their cytoplasmic domains suggests that FCRL molecules play a role in coordinating immune responses, contributing to the maintenance of the delicate balance required to initiate or terminate effector functions while limiting collateral damage to host tissues. In this thesis, I investigated the role of FCRL3, one of the few FCRL family members expressed by T lymphocytes. A functional variant of FCRL3, defined by a single nucleotide polymorphism (SNP) in the FCRL3 promoter region, has been associated to several autoimmune diseases; however, FCRL3 function and mechanistic contribution to conventional T lymphocytes biology remained poorly defined. To address this, we performed an extensive functional characterization of the subsets of T lymphocytes expressing FCRL3. Our results across conventional T lymphocytes revealed that FCRL3 marks highly differentiated T cells with reduced proliferative and activation capacity but enhanced cytotoxic potential. Furthermore, using CRISPR-Cas9–mediated gene editing and ectopic expression approaches, we identified a direct role for FCRL3 in the negative regulation of T cell activation. Collectively, these findings advance our understanding of how FCRL3 expression influences T cell effector function, providing novel insights into its potential contribution to immune regulation and autoimmunity.
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  • English
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Medicine
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https://n2t.net/ark:/12658/srd1335550
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