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Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE249734 | GEO | 2024/11/11

REPOSITORIES: GEO

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Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response

Project description:Adoptive transfer of immune cells expressing chimeric antigen receptors (CARs) is an effective therapy for B-lineage malignancies. However, most patients will relapse and this therapeutic has yet to show strong efficacy in other hematologic or solid tumors. One opportunity for improvement lies in the ability to select or generate T cells that have the highest potential for potent anti-tumor responses and T cell persistence. Here, we dissect the biology of CD8+ CAR T cells by controlling whether the T cell has encountered cognate TCR antigen prior to CAR generation. We find that prior antigen experience influences multiple aspects of in vitro and in vivo CAR T cell functionality, boosting effector function and leukemia clearance in the setting of limiting target antigen density. However, this comes at the expense of proliferative capacity, resistance to dysfunction, and clearance of wildtype leukemia in the setting of limiting CAR+ cell dose. Epigenetic and transcriptomic comparisons of these cell populations uncover that modulation of the Runx2 transcription factor differentially impacts CAR T cell functionality depending on prior cell state. Collectively, our data demonstrate that prior antigen experience status determines functional attributes of a CAR T cell, as well as amenability to functional enhancement by transcription factor modulation.

2024-11-14 | GSE281486 | GEO

Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response [ATAC-Seq]

2024-11-14 | GSE281588 | GEO

Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response [ATAC-seq]

2024-11-10 | GSE249733 | GEO

Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response [RNA-seq]

2024-11-10 | GSE249732 | GEO

Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response

Project description:Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response

| PRJNA1184132 | ENA

Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response

Project description:Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response

| PRJNA1050258 | ENA

Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response [RNA-seq]

Project description:Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response [RNA-seq]

| PRJNA1050261 | ENA

Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response [ATAC-seq]

Project description:Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response [ATAC-seq]

| PRJNA1050260 | ENA

Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response [ATAC-Seq]

Project description:Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response [ATAC-Seq]

| PRJNA1184767 | ENA

Cognate antigen directs CD8+ T cell migration to vascularized transplants.

Project description:The migration of effector or memory T cells to the graft is a critical event in the rejection of transplanted organs. The prevailing view is that the key steps involved in T cell migration - integrin-mediated firm adhesion followed by transendothelial migration - are dependent on the activation of Gαi-coupled chemokine receptors on T cells. In contrast to this view, we demonstrated in vivo that cognate antigen was necessary for the firm adhesion and transendothelial migration of CD8+ effector T cells specific to graft antigens and that both steps occurred independent of Gαi signaling. Presentation of cognate antigen by either graft endothelial cells or bone marrow-derived APCs that extend into the capillary lumen was sufficient for T cell migration. The adhesion and transmigration of antigen-nonspecific (bystander) effector T cells, on the other hand, remained dependent on Gαi, but required the presence of antigen-specific effector T cells. These findings underscore the primary role of cognate antigen presented by either endothelial cells or bone marrow-derived APCs in the migration of T cells across endothelial barriers and have important implications for the prevention and treatment of graft rejection.

| S-EPMC3668847 | biostudies-literature

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