De Rosa, Giusy (2024) Intra- and extracellular tuning of the amino acid transporter SLC7A11 in the control of Regulatory T cell homeostasis. [Tesi di dottorato]

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Abstract

Human CD4+CD25+Foxp3+ Treg cells are a subset of CD4+ T cells which control immunological self-tolerance by inhibiting autoreactive cell responses, thus playing a key role in the pathogenesis of autoimmune diseases. In this study, we found that signals of pseudo-starvation reversed human Treg cell in vitro anergy modulating a plethora of transcripts involved in intra-extracellular transport and solute carriers (SLC). Our data suggest a possible mechanism accounting for progressive loss of Treg cells in autoimmunity, identifying SLC7A11 as a crucial molecular modulator of Treg cell homeostasis and proliferation. Treg cells can carry out their inhibitory function through several mechanisms, including the production of extracellular vesicles (EVs). We found that human Treg-EVs are enriched of miR-142-3p, a microRNA whose shuttling in EV-target cells is involved in down-regulation of mRNAs necessary to engage cell growth, including SLC7A11, which we demonstrated to be a direct target of miR-142-3p. In conclusion, our results describe a previously unrecognized mechanism for Treg cell suppressive activity, elucidating a critical role of miR-142-3p shuttling by Treg cells via EVs in the regulation of SLC7A11 in the target cells. The miR-142-3p/SLC7A11 loop can therefore represent a possible therapeutic target to improve Treg cell function in autoimmune diseases.

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