Biology subjects

Kropp, K. N.

Publications and source records attributed to Kropp, K. N..

3 recordsLinked to original sources

bioRxiv2026

Mitochondrial ATP production promotes T cell differentiation and function by regulating chromatin accessibility

Immune elimination of chronic infection or cancer requires cytotoxic CD8+ T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process and T cells subjected to chronic antigen exposure have compromised effector function despite high rates of glycolysis. Here we report the ability of the short-chain -hydroxy acid, D--hydroxybutyrate, to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation, even in glucose-replete media. This conversion suppresses both AMPK phosphorylation and the integrated stress response (ISR) in activated T cells while significantly elevating the level of the phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induction of CD8-effector gene transcription was coupled to bioenergetics by enhanced ATP-dependent remodeling of chromatin accessibility at effector gene loci. DAHB enhanced CD8+ T cell antitumor activity both in vitro and in vivo, and DAHB treatment of transferred T cells led to persistent in vivo antitumor effects. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.

immunology↗

bioRxiv2026

A post-translational regulatory map of chronic antigen-driven human T cell dysfunction.

T cells exposed to persistent antigen in the context of chronic viral infections or cancer lose self-renewal and cytotoxic capacity. Several transcriptional, epigenetic, and metabolic drivers of this process have been identified. However, the post-transcriptional regulatory mechanisms influencing the proteome of dysfunctional T cells are not well understood. Here we present a time-resolved molecular landscape of human T cells during the development of chronic antigen-driven dysfunction. Persistent T cell receptor stimulation significantly remodeled the proteome, including changes in canonical T cell exhaustion-associated proteins and proteins related to mitochondrial function, redox homeostasis, nucleotide metabolism, and cell-cycle progression. Dysfunctional T cells displayed activation of stress response pathways that were recapitulated in vivo; targeting these pathways altered the cytotoxic capacity of T cells during persistent tumor exposure. Our comprehensive proteomic resource reveals unique post-transcriptional changes in dysfunctional T cells and lays the groundwork for novel cysteine-directed therapeutics to enhance cancer immunotherapy.

immunology↗

bioRxiv2024

CAR-engineered lymphocyte persistence is governed by a FAS ligand/FAS auto-regulatory circuit

Chimeric antigen receptor (CAR)-engineered T and NK cells can cause durable remission of B-cell malignancies; however, limited persistence restrains the full potential of these therapies in many patients. The FAS ligand (FAS-L)/FAS pathway governs naturally-occurring lymphocyte homeostasis, yet knowledge of which cells express FAS-L in patients and whether these sources compromise CAR persistence remains incomplete. Here, we constructed a single-cell atlas of diverse cancer types to identify cellular subsets expressing FASLG, the gene encoding FAS-L. We discovered that FASLG is limited primarily to endogenous T cells, NK cells, and CAR-T cells while tumor and stromal cells express minimal FASLG. To establish whether CAR-T/NK cell survival is regulated through FAS-L, we performed competitive fitness assays using lymphocytes modified with or without a FAS dominant negative receptor ({Delta}FAS). Following adoptive transfer, {Delta}FAS-expressing CAR-T and CAR-NK cells became enriched across multiple tissues, a phenomenon that mechanistically was reverted through FASLG knockout. By contrast, FASLG was dispensable for CAR-mediated tumor killing. In multiple models, {Delta}FAS co-expression by CAR-T and CAR-NK enhanced antitumor efficacy compared with CAR cells alone. Together, these findings reveal that CAR-engineered lymphocyte persistence is governed by a FAS-L/FAS auto-regulatory circuit.

immunology↗