Intrathymic Notch Signaling Co-ordinates Multiple Unconventional T Cell Effector Cell Fate Choices

Cynthia Guidos, PhD
Senior Scientist 
Program in Cell & Systems Biology
SickKids University Heath Network

Professor
Department of Immunology
University of Toronto
Toronto, ON, Canada

This conference is hosted by Tarik Möröy, PhD. This conference is part of the 2025-2026 IRCM conference calendar.

About this conference
Notch signaling is required during early T cell development to produce large numbers of TCαβ⁺ CD4⁺CD8⁺ (DP) thymocytes, but is dispensable for their selection into conventional CD4 and CD8αβ (here referred to as CD8) T cell lineages. However, it is not known how Notch impacts “agonist” selection of strongly self-reactive DP precursors. This process produces “unconventional” innate effector memory (IEM) T cell lineages armed with pre-programmed T helper (TH) or cytotoxicity (T_C) effector functions. They include natural killer T (NKT) cells, CD4-CD8- (DN) precursors of CD8αα intraepithelial lymphocytes (DN IELp) and certain TCRγδ lineages. Most do not re-circulate but remain in the thymus or migrate to barrier sites where they function as “poised” responders to tissue stress, infection and cancer. Molecular mechanisms that elicit specific immune effector and tissue residency (TR) programs during agonist selection of IEM T cells are undefined.

To address these gaps in knowledge, we created new mouse models that use CD4Cre to activate or inhibit Notch signaling in DP thymocytes. Ectopic Notch activation induced generation of cells resembling CD8αα IEL, whereas Notch inactivation impaired differentiation of neonatal DN IELp, their thymic precursors. Notch inactivation also altered T_H vs T_C effector fate choices and expression of TR programs during agonist selection of DN IELp, NKT and NKT-like TCRγδ lineages. These findings identify Notch as a global microenvironmental determinant of immune effector fate choices and TR programs during agonist selection. They also have broad implications for efforts to manufacture of “off-the-shelf” human T cell therapies armed with specific immune effector functions and re-circulating versus TR programs. 

About Cynthia Guidos
Cynthia Guidos is an immunologist and leukemia biologist whose research aims to elucidate basic mechanisms of lymphocyte development and differentiation, and to define how defects in these processes cause immune-mediated diseases and contribute to leukemia initiation and progression. She also established and directs the Center for Advanced Single Cell Analysis (CASCA) at SickKids, which provides advanced technical platforms to perform “deep” immune profiling using "next-generation" mass spectrometry-coupled flow cytometry (CyTOF) and single cell RNA-sequencing (scRNA-Seq).

Her group uses these and other high content single cell analysis platforms coupled with in vivo and in vitro models to analyze how genetic perturbations impact immune cell phenotypes, functions and molecular programs. 

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