Human-engineered Treg-like cells suppress FOXP3-deficient T cells but preserve adaptive immune responses in vivo.

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Scientific Abstract:
Objectives: Genetic or acquired defects in FOXP3(+) regulatory T cells (Tregs) play a key role in many immune-mediated diseases including immune dysregulation polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Previously, we demonstrated CD4(+) T cells from healthy donors and IPEX patients can be converted into functional Treg-like cells by lentiviral transfer of FOXP3 (CD4(LVFOXP3)). These CD4(LVFOXP3) cells have potent regulatory function, suggesting their potential as an innovative therapeutic. Here, we present molecular and preclinical in vivo data supporting CD4(LVFOXP3) cell clinical progression. Methods: The molecular characterisation of CD4(LVFOXP3) cells included flow cytometry, qPCR, RNA-seq and TCR-seq. The in vivo suppressive function of CD4(LVFOXP3) cells was assessed in xenograft-versus-host disease (xeno-GvHD) and FOXP3-deficient IPEX-like humanised mouse models. The safety of CD4(LVFOXP3) cells was evaluated using peripheral blood (PB) humanised (hu)- mice testing their impact on immune response against pathogens, and immune surveillance against tumor antigens. Results: We demonstrate that the conversion of CD4(+) T cells to CD4(LVFOXP3) cells leads to specific transcriptional changes as compared to CD4(+) T-cell transduction in the absence of FOXP3, including upregulation of Treg-related genes. Furthermore, we observe specific preservation of a polyclonal TCR repertoire during in vitro cell production. Both allogeneic and autologous CD4(LVFOXP3) cells protect from xeno-GvHD after two sequential infusions of effector T cells. CD4(LVFOXP3) cells prevent hyper-proliferation of CD4(+) memory T cells in the FOXP3-deficient IPEX-like hu-mice. CD4(LVFOXP3) cells do not impede in vivo expansion of antigen-primed T cells or tumor clearance in the PB hu-mice. Conclusion: These data support the clinical readiness of CD4(LVFOXP3) cells to treat IPEX syndrome and other immune-mediated diseases caused by insufficient or dysfunctional FOXP3(+) Tregs.