Characterisation and impact of kidney-resident Tregs in kidney physiology and pathologies

Descripción del proyecto

Linfocitos T reguladores residentes en el riñón en la salud y la enfermedad

Los pacientes que padecen una insuficiencia renal crónica o terminal suelen necesitar a menudo un trasplante de riñón para curarse. Los linfocitos T reguladores (Treg) se han propuesto como un medio para inducir tolerancia específica del tejido a modo de alternativa a la inmunosupresión sistémica después del trasplante. Al mismo tiempo, estas células protegen de lesiones y promueven la reparación tisular. Con todo, aún no está claro si este efecto está mediado por los Treg residentes en el tejido o los que están en circulación. El proyecto financiado con fondos europeos Kidney-Treg caracterizará los Treg en el riñón utilizando técnicas de biología molecular punteras y determinará su impacto en la fisiología del riñón. El objetivo principal es examinar las funciones de estas células residentes en el riñón como nuevas herramientas terapéuticas.

Objetivo

Tregs are a subtype of T cells exerting immunosuppressive functions that are vital to prevent autoimmunity. Recently, tissue-resident Tregs have been proposed to be phenotypically and functionally distinct from the generic Tregs in circulation. Systemic Treg supplementation and depletion studies strongly support a role for Tregs in protection from injury and promotion of tissue repair in models of kidney diseases, highlighting the potential of harnessing Tregs in these pathologies. However, due to the systemic nature of the Treg manipulation in these studies, it is unknown if the effect resides in systemic impacts or in tissue-based impacts. The aim of this project is to characterise Tregs located in the kidney and to expand the kidney-resident Treg population, without impacting the systemic population, in order to evaluate their specific impact on the physiology and pathologies of the kidney. First, I will characterise the kidney-resident Tregs using state-of-the-art molecular biology techniques, such as scRNAseq, and an innovative mouse model of cell fate mapping based on a photoactivatable Cre-recombinase. Second, I will evaluate their specific functions in physiology and pathologies of the kidney using a mouse model of tissue-specific Treg expansion uniquely available in the host laboratory. As well as the novel biology exploring the potential functions of kidney-resident Tregs, the distinction between systemic and kidney-based effects is critical to develop new therapeutic tools aiming to target kidney-resident Tregs. The induction of tissue-specific tolerance for kidney autoimmunity or transplantation, without inducing systemic immune suppression, constitute a promising and feasible alternative to existing immunosuppressive therapies. The knowledge and experience gained from this project combined with my scientific and personal development will give me all the skills I need to achieve my objective to pursue an exciting scientific career in academia.