Biology subjects

Hoefakker, K.

Publications and source records attributed to Hoefakker, K..

3 recordsLinked to original sources

bioRxiv2023

An "alert state" ribosome population acts as a master regulator of cytokine mediated processes

Inflammatory cytokines are pivotal to immune responses. Upon cytokine exposure, cells enter an "alert-state" that enhances their visibility to the immune system. Here, we identified an "alert-state" subpopulation of ribosomes (ASRs) defined by the presence of the P-stalk. We show that ASRs are formed in response to cytokines linked to tumor immunity, and are involved in the preferential translation of mRNAs vital for the cytokine response. Mechanistically, ASRs are required for the efficient translation of transmembrane domains of receptor molecules involved in cytokine-mediated processes. Importantly, loss of the ASR prevents CD8+ T cell recognition and killing, and inhibitory cytokines like TGF{beta} hinder ASR formation, suggesting that the ASR is a central regulatory hub upon which multiple signals converge. Thus, the ASR is an essential mediator of the cellular rewiring that occurs following cytokine exposure, via the translational regulation of this process.

immunology↗

bioRxiv2020

Healthy cells functionally present TAP-independent SSR1 peptides: implications for selection of clinically relevant antigens

Tumors with an impaired transporter associated with antigen processing (TAP) present several ER-derived self-antigens on HLA class I (HLA-I) which are absent on healthy cells. Selection of such TAP-independent antigens for T cell-based immunotherapy should include analysis of their expression on healthy cells to prevent therapy-induced adverse toxicities. However, it is unknown how the absence of clinically relevant antigens on healthy cells needs to be validated. Here we monitored TAP-independent antigen presentation on various healthy cells using a new toolbox consisting of a T cell clone recognizing a TAP-independent SSR1-derived antigen. We found that most but not all healthy cells present this antigen under normal and inflammatory conditions, indicating that TAP-independent antigen presentation is a variable phenomenon. Our data emphasize the necessity of extensive testing of a wide variety of healthy cell types to define clinically relevant TAP-independent antigens that can be safely targeted by immunotherapy.

immunology↗

bioRxiv2020

PAKC: A novel Panel of HLA class I Antigen presentation machinery Knockout Cells from the same genetic origin

With the emergence of immunotherapies, the understanding of functional HLA class I antigen presentation to T cells is more relevant than ever. Current knowledge on antigen presentation is based on decades of research in a wide variety of cell types with varying antigen presentation machinery (APM) expression patterns, proteomes and HLA haplotypes. This diversity complicates the establishment of individual APM contributions to antigen generation, selection and presentation. Therefore, we generated a novel Panel of APM Knockout Cell lines (PAKC) from the same genetic origin. After CRISPR/Cas9 genome-editing of ten individual APM components in a human cell line, we derived clonal cell lines and confirmed their knockout status and phenotype. We then show how PAKC will accelerate research on the functional interplay between APM components and their role in antigen generation and presentation. This will lead to improved understanding of peptide-specific T cell responses in infection, cancer and autoimmunity. Key pointsO_LIWe generated a panel of cell lines to study HLA class I antigen presentation C_LIO_LIWe show how this will spark research in infection, tumor biology and autoimmunity C_LI

immunology↗