The Badr laboratory at CIMR investigates fundamental mechanisms that safeguard the immune system from self-reactivity. By focusing on autoreactive T cells, we aim to uncover how tolerance is established and maintained, and how its failure contributes to human disease. Our long-term vision is to translate these insights into innovative therapies for autoimmunity and cancer.
1. Investigate molecular and cellular mechanisms that regulate autoreactive T cell fate during thymic development and in peripheral tissues.
2. Define the role of autoreactive T cells in autoimmune diseases, with a focus on multiple sclerosis, type 1 diabetes, and autoimmune hepatitis.
3. Elucidate how tolerized autoreactive T cells influence tumor immune evasion and evaluate their reprogramming potential for cancer immunotherapy.
4. Translate findings from mouse models into human studies using tissue organoids, single-cell transcriptomics, and TCR sequencing to identify therapeutic targets.
1. Discovery of Clonal Eviction as a novel mechanism for autoreactive T cell tolerance — revealed that autoreactive CD8 T cells are not deleted in the thymus but instead prematurely exported as immature precursors that later differentiate into self-tolerant regulatory-like cells, redefining the classical view of central tolerance (Science, 2023).
2. Pathways controlling effector and helper T cell programming — identified CRTAM as a key driver of CD4⁺ cytotoxic T cell lineage commitment and uncovered nucleic acid sensing as a trigger for Th2 differentiation, providing new insights into how signals shape T cell fate (J Exp Med, 2016; Nat Commun, 2014).
3. Role of chemokine signaling in central tolerance — demonstrated how Sirpα⁺ dendritic cells and the chemokine receptor CCR2 orchestrate thymic tolerance and facilitate tumor immune evasion, highlighting the intersection of central tolerance and cancer biology (PLoS One, 2012).
Badr M#, Zhang Z, Tai X, Singer A#. CD8 T cell tolerance results from eviction of immature autoreactive cells from the thymus. Science, 2023, 382: 534–541. DOI: 10.1126/science.adh4124
Badr M, Hata K, Furuhata M, Toyota H, Yokosuka T. The multifaceted role of PD-1 in health and disease. In: Miyasaka M, Takatsu K (eds). Chronic Inflammation. Springer, Tokyo. 2016: 441–457.
Takeuchi A, Badr M, Miyauchi K, Ishihara C, Onishi R, Guo Z, Sasaki Y, Ike H, Takumi A, Tsuji N, Murakami Y, Katakai T, Kubo M, Saito T. CRTAM determines the CD4⁺ cytotoxic T lymphocyte lineage. J Exp Med, 2016, 213: 123–138. DOI: 10.1084/jem.20150519
Imanishi T, Ishihara C, Badr M, Hashimoto-Tane A, Kimura Y, Kawai T, Takeuchi O, Ishii KJ, Taniguchi S, Noda T, Hirano H, Brombacher F, Barber GN, Akira S, Saito T. Nucleic acid sensing by T cells initiates Th2 cell differentiation. Nat Commun, 2014, 5: 3566. DOI: 10.1038/ncomms4566
Baba T, Badr M, Tomaru U, Ishizu A, Mukaida N. Novel process of intrathymic tumor immune tolerance through CCR2-mediated recruitment of Sirpα⁺ dendritic cells: a murine model. PLoS One, 2012, 7: e41154. DOI: 10.1371/journal.pone.0041154