Characterization of thymic involution and how it contributes to immunosenescence in mice

• Grant number: 23/01703-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2023
• End date: March 31, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Marcelo Alves da Silva Mori
• Grantee: Niedson Correia de Lima Junior
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 21/08354-2 - The interplay between the immune system and metabolism as a key determinant of the aging process, AP.TEM

Abstract

The thymus plays a central role in generating the T cells repertoire - a phenomenon orchestrated by thymic epithelial cells (TECs). The proper functionality of the selection processes exerted by TECs is crucial to guarantee a functional pool of effector T cells. Interestingly, selection occurs prior to puberty, before the thymus begins involuting and lymphostromal thymic zones are progressively substituted by adipocytes and thymic function is markedly impaired. Consequently, the pool of circulating naive T cells progressively reduces with aging and T cells start exhibiting phenotypes of exhaustion or immunosenescence. Overall, this contributes to immunological aging and, potentially, to organismal aging. Whereas this is a widely conserved phenomenon occurring in most vertebrates and coupled with reproduction and nutrition, thus suggesting it is a biologically relevant phenomenon, how the thymus undergoes drastic histological changes and how this contributes to immunity and aging remains largely unknown. While it is well documented that obesity accelerates thymic involution and dietary restriction slows it down, work by our group suggests that miRNAs may play a role in this phenomenon at the molecular level. miRNAs are key regulators of adipogenesis and control many features related to aging. miRNA biogenesis, particularly at the level of the type III endoribonuclease DICER, is induced in adipose tissue by interventions that promote longevity (e.g., dietary restriction and exercise) and impaired by obesity and aging. We and others have also demonstrated the potential of miRNAs (particularly from adipocytes) to be secreted and mediate intertissue communication. Our preliminary results show that mice deficient in DICER in TECs (Foxn1_cre x Dicer_flox) exhibit disrupted T cell repertoire and altered thymic architecture, indicating an important role of miRNAs controlling the functionality of TECs and the generation of a proper T cell repertoire. Our preliminary data also indicate that thymic adipocytes originate from TECs. Therefore, it is our intention to evaluate how aging affects miRNA levels in the thymus and further investigate how miRNAs contribute to thymic adipogenesis and T cell maturation.