Deciphering the developmental requirements of CD4+ tissue-resident memory T cells
Final Report Abstract
The immune system of the human body consists of approximately 1.8 trillion cells, commonly referred to as white blood cells. However, during the last decades, it became clear that most of these cells are located and acting within body tissues, rather than in the blood. This is true for more than 95 % of T cells, which are central in mediating immunity against infections and cancer. Although the vast majority of T cells is patrolling tissues, during an immune response, a specific subset of T cells acquires the ability to permanently reside there. Providing long-lasting immunological memory, these quiescent long-lasting T cells were consequently termed tissue-resident memory T cells (TRM). These cells form after primary antigen encounter along circulating memory T cells (T CIRC) and provide long-term protection against antigen re-encounter at barrier sites. TRM have gained increased attention over recent years given the association of this T cell subset with positive survival outcomes in infections and cancer but may be detrimental in autoimmune conditions. Since their first description, T RM have been detected in most tissues of the human body using e.g. CD69 and integrin alpha E (CD103), which are generally considered a hallmarks of TRM and facilitate retention within peripheral tissues, including the gastrointestinal and hepatobiliary tracts. However, it has recently been shown that TRM across different tissue sites display distinct phenotypes, i.e. expression levels of CD103, with hepatic T RM showing little to no expression of this molecule. These phenotypic differences could be linked to different tissue microenvironments and an associated differential availability of TRM-shaping signals across tissues. One such signal is the vitamin A derivative retinoic acid (RA). We recently showed that RA not only synergises with transforming growth factor beta (TGFb), the widely considered major driver of tissue residency in T cells, in instructing TRM formation but importantly maintains TRM abundance and quiescence within the liver and the intestines. These findings significantly pave the way towards targeting tissue-resident T cells in an organ-specific manner, which is an unmet need for immune-mediated diseases, e.g. of the hepatobiliary tract.
Publications
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Retinoic acid and TGF-β orchestrate organ-specific programs of tissue residency. Immunity, 57(11), 2615-2633.e10.
Obers, Andreas; Poch, Tobias; Rodrigues, Grace; Christo, Susan N.; Gandolfo, Luke C.; Fonseca, Raissa; Zaid, Ali; Kuai, Joey En Yu; Lai, Hongjin; Zareie, Pirooz; Yakou, Marina H.; Dryburgh, Lachlan; Burn, Thomas N.; Dosser, James; Buquicchio, Frank A.; Lareau, Caleb A.; Walsh, Calum; Judd, Louise; Theodorou, Maria Rafailia ... & Mackay, Laura K.
