9 research outputs found
Force Generation upon T Cell Receptor Engagement
T cells are major players of adaptive immune response in mammals. Recognition of
an antigenic peptide in association with the major histocompatibility complex at
the surface of an antigen presenting cell (APC) is a specific and sensitive
process whose mechanism is not fully understood. The potential contribution of
mechanical forces in the T cell activation process is increasingly debated,
although these forces are scarcely defined and hold only limited experimental
evidence. In this work, we have implemented a biomembrane force probe (BFP)
setup and a model APC to explore the nature and the characteristics of the
mechanical forces potentially generated upon engagement of the T cell receptor
(TCR) and/or lymphocyte function-associated antigen-1 (LFA-1). We show that upon
contact with a model APC coated with antibodies towards TCR-CD3, after a short
latency, the T cell developed a timed sequence of pushing and pulling forces
against its target. These processes were defined by their initial constant
growth velocity and loading rate (force increase per unit of time). LFA-1
engagement together with TCR-CD3 reduced the growing speed during the pushing
phase without triggering the same mechanical behavior when engaged alone.
Intracellular Ca2+ concentration
([Ca2+]i) was monitored simultaneously
to verify the cell commitment in the activation process.
[Ca2+]i increased a few tens of seconds
after the beginning of the pushing phase although no strong correlation appeared
between the two events. The pushing phase was driven by actin polymerization.
Tuning the BFP mechanical properties, we could show that the loading rate during
the pulling phase increased with the target stiffness. This indicated that a
mechanosensing mechanism is implemented in the early steps of the activation
process. We provide here the first quantified description of force generation
sequence upon local bidimensional engagement of TCR-CD3 and discuss its
potential role in a T cell mechanically-regulated activation process
SUV39H1 Ablation Enhances Long-term CAR T Function in Solid Tumors.
Failure of adoptive T-cell therapies in patients with cancer is linked to limited T-cell expansion and persistence, even in memory-prone 41BB-(BBz)-based chimeric antigen receptor (CAR) T cells. We show here that BBz-CAR T-cell stem/memory differentiation and persistence can be enhanced through epigenetic manipulation of the histone 3 lysine 9 trimethylation (H3K9me3) pathway. Inactivation of the H3K9 trimethyltransferase SUV39H1 enhances BBz-CAR T cell long-term persistence, protecting mice against tumor relapses and rechallenges in lung and disseminated solid tumor models up to several months after CAR T-cell infusion. Single-cell transcriptomic (single-cell RNA sequencing) and chromatin opening (single-cell assay for transposase accessible chromatin) analyses of tumor-infiltrating CAR T cells show early reprogramming into self-renewing, stemlike populations with decreased expression of dysfunction genes in all T-cell subpopulations. Therefore, epigenetic manipulation of H3K9 methylation by SUV39H1 optimizes the long-term functional persistence of BBz-CAR T cells, limiting relapses, and providing protection against tumor rechallenges.
Limited CAR T-cell expansion and persistence hinders therapeutic responses in solid cancer patients. We show that targeting SUV39H1 histone methyltransferase enhances 41BB-based CAR T-cell long-term protection against tumor relapses and rechallenges by increasing stemness/memory differentiation. This opens a safe path to enhancing adoptive cell therapies for solid tumors. See related article by Jain et al., p. 142. This article is featured in Selected Articles from This Issue, p. 5
X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene
BACKGROUND: We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections. OBJECTIVE: We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency. METHODS: We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment. RESULTS: We observed hemizygous mutations in the moesin (MSN) gene (located on the X chromosome and coding for MSN) in all 7 patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in the MSN four-point-one, ezrin, radixin, moesin domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naive T-cell counts were particularly low for age, and most CD8(+) T cells expressed the senescence marker CD57. This phenotype was associated with impaired T-cell proliferation, which was rescued by expression of wild-type MSN. MSN-deficient T cells also displayed poor chemokine receptor expression, increased adhesion molecule expression, and altered migration and adhesion capacities. CONCLUSION: Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency