Biology subjects

Fuentealba, J.

Publications and source records attributed to Fuentealba, J..

3 recordsLinked to original sources

bioRxiv2024

The DivisionCounter, a method for counting large ranges of cell divisions in vivo, reveals cell dynamics of leukemic cell killing via CAR-T therapy

Cell division drives multicellular growth and its dysregulation can cause disease. While approximately 44 divisions are needed to produce without death all 1013 cells in the human body, current methods are limited to count 10 cell divisions in vivo across diverse mammalian cell types. Here we introduce the DivisionCounter, a method to count cell division in vivo over large division ranges ([~]70 divisions) using an easy fluorescence readout. We demonstrate that the DivisionCounter accurately measures the average cell division count of cells both in vitro and in vivo. Its use revealed that leukemia tumor division rates are independent of the organs specific microenvironment and CAR-T cell treatment, providing an estimate of tumor death rates in vivo. The DivisionCounter method holds unique potential for quantifying contributions of cell division, death, and migration to the growth of healthy and pathological mammalian tissues.

immunology↗

bioRxiv2024

Epigenetic control of CD8+ T cell tissue homing and tissue resident memory T cell precursors by the histone methyltransferase SUV39H1

Activation of CD8+ T cells leads to the differentiation of short-lived terminal effectors and memory precursors. Some of these memory precursors remain in lymphoid organs and become long-lived central memory T cells (TCM), while others home to non-lymphoid peripheral tissues early after antigen recognition and differentiate into tissue resident memory T cells (TRM). The early stages of memory precursor tissue homing and TRM differentiation remain poorly understood. We show here that at steady state, during space-induced "homeostatic" expansion, and after flu infection, deletion of the histone 3-lysine 9 methyltransferase SUV39H1 in CD8+ T cells, increases the homing to non-lymphoid tissues (including liver, lungs, gut and skin). SUV39H1-defective cells in tissues express CD49d and differentiate into CD69+/CD103-TRM after adoptive transfer or Flu infection. SUV39H1-defective T cells that accumulate in lungs are fully functional in both Flu re-infection and lung tumor models. We conclude that SUV39H1 restrains CD8+ T cell tissue homing and TRM differentiation in WT mice. These results should encourage the use of SUV39H1-depletion in the context of adoptive T cell therapies to enhance tissue homing, thereby optimizing the efficiency of target cell eradication and long-term protection in the context of infection and cancer.

immunology↗

bioRxiv2021

In vivo genome-wide CRISPR screens identify SOCS1 as a major intrinsic checkpoint of CD4+ Th1 cell response

The expansion of antigen experienced CD4+ T cells is limited by intrinsic factors. Using in vivo genome-wide CRISPR-Cas9 screens, we identified SOCS1 as a non-redundant checkpoint imposing a brake on CD4+ T-cell proliferation upon rechallenge. We show here that SOCS1 is a critical node integrating both IL-2 and IFN-{gamma} signals and blocking multiple signaling pathways to abrogate CD4+ Th1 cell response. In CD8+ T-cell, SOCS1 does not impact the proliferation but rather reduces survival and effector functions. By targeting SOCS1, both murine and human CD4+ T-cell antitumor adoptive therapies exhibit a restored intra-tumor accumulation, proliferation/survival, persistence and polyfunctionality, promoting long term rejection of established tumors. These findings identify SOCS1 as a major intracellular checkpoint inhibitor of primed CD4+ T cells, opening new possibilities to optimize CAR-T cell therapies composition and efficacy.

immunology↗