Biology subjects

Scott-Browne, J.

Publications and source records attributed to Scott-Browne, J..

3 recordsLinked to original sources

bioRxiv2023

TGF-β broadly modifies rather than specifically suppresses reactivated memory CD8 T cells in a dose-dependent manner

Transforming growth factor {beta} (TGF-{beta}) directly acts on naive, effector and memory T cells to control cell fate decisions, which was shown using genetic abrogation of TGF-{beta} signaling. TGF-{beta} availability is altered by infections and cancer, however the dose-dependent effects of TGF-{beta} on memory CD8 T cell (Tmem) reactivation are still poorly defined. We examined how activation and TGF-{beta} signals interact to shape the functional outcome of Tmem reactivation. We found that TGF-{beta} could suppress cytotoxicity in a manner that was inversely proportional to the strength of the activating TCR or pro-inflammatory signals. In contrast, even high doses of TGF-{beta} had a comparatively modest effect on IFN-{gamma} expression in the context of weak and strong reactivation signals. Since CD8 Tmem may not always receive TGF-{beta} signals concurrently with reactivation, we also explored whether the temporal order of reactivation versus TGF-{beta} signals is of importance. We found that exposure to TGF-{beta} prior to as well as after an activation event were both sufficient to reduce cytotoxic effector function. Concurrent ATAC-seq and RNA-seq analysis revealed that TGF-{beta} altered [~]10% of the regulatory elements induced by reactivation and also elicited transcriptional changes indicative of broadly modulated functional properties. We confirmed some changes on the protein level and found that TGF-{beta}-induced expression of CCR8 was inversely proportional to the strength of the reactivating TCR signal. Together, our data suggest that TGF-{beta} is not simply suppressing CD8 Tmem, but modifies functional and chemotactic properties in context of their reactivation signals and in a dose-dependent manner.

immunology↗

bioRxiv2020

Single-cell RNA transcriptomics identifies Hivep3 as essential in regulating the development of innate-like T lymphocytes

Most T lymphocytes leave the thymus as naive cells with limited functionality. However, unique populations of T cells, commonly known as innate-like T cells, differentiate into functionally distinct effector subsets during thymic development under the influence of the transcription factor PLZF. Here, we profiled >10,000 differentiating thymic iNKT cells using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of their maturation, function, and fate decision in steady state. We identified Hivep3, a zinc finger transcription factor and adaptor protein, as a key factor that is expressed in early precursors and regulates the post-selection proliferative burst, differentiation and functions of iNKT cells. Importantly, we extended these results to other PLZF+ innate-like T cell populations, highlighting the unique and common requirement of Hivep3 to the development of all innate-like T cells.

immunology↗

bioRxiv2017

The somatically generated T cell receptor CDR3a contributes to the MHC allele specificity of the T cell receptor

Mature T cells bearing {beta} T cell receptors react with foreign antigens bound to alleles of major histocompatibility complex proteins (MHC) that they were exposed to during their development in the thymus, a phenomenon known as positive selection. The structural basis for positive selection has long been debated. Here, using mice expressing one of two different T cell receptor {beta} chains and various MHC alleles, we show that positive selection-induced MHC bias of T cell receptors is affected both by the germline encoded elements of the T cell receptor and {beta} chain and, surprisingly, dramatically affected by the non germ line encoded CDR3 of the T cell receptor chain. Thus, in addition to determining specificity for antigen, the non germline encoded elements of T cell receptors may help the proteins cope with the extremely polymorphic nature of major histocompatibility complex products within the species.

immunology↗