Biology subjects

Minguet, S.

Publications and source records attributed to Minguet, S..

4 recordsLinked to original sources

bioRxiv2023

TCR/CD3-based synthetic antigen receptors (TCC) convey superior antigen sensitivity combined with high fidelity of activation

Low antigen sensitivity and a gradual loss of effector functions limit the clinical applicability of chimeric antigen receptor (CAR)-modified T-cells and call for alternative antigen receptor designs for effective T-cell-based cancer immunotherapy. Here we applied advanced microscopy to demonstrate that TCR/CD3-based synthetic constructs (TCC) outperform second-generation CAR formats with regard to conveyed antigen sensitivities by up to a thousand-fold. TCC-based antigen recognition occurred without adverse non-specific signaling, which is typically observed in CAR-T-cells, and did not depend - unlike sensitized peptide/MHC detection by conventional T-cells - on CD4- or CD8- coreceptor engagement. TCC-endowed signaling properties may prove critical when targeting antigens in low abundance and aiming for a durable anti-cancer response.

immunology↗

bioRxiv2022

Kidins220 promotes thymic iNKT cell development by reducing TCR signals, but enhances TCR signals in splenic iNKT cells

The stepwise development of thymic invariant natural killer T (iNKT) cells is controlled by the TCR signal strength. The scaffold protein Kinase D interacting substrate of 220 kDa (Kidins220) binds to the TCR regulating TCR signaling. T cell-specific Kidins220 knock-out (T-KO) mice contain severely decreased iNKT numbers. Very early in iNKT development TCR signals are reduced in the T-KO. In later steps, TCR signaling is increased in the T-KO leading to enhanced apoptosis of iNKT cells. Kidins220s absence affects the iNKT1 subset most as it requires the weakest TCR signals for development. We also show that in iNKT1 development, weak TCR signals promote the progressive loss of CD4. In the periphery, Kidins220 switches its role back to promoting TCR signaling as splenic T-KO iNKT cells produce less cytokines and show reduced TCR signaling after in vivo stimulation with -galactosylceramide. In conclusion, Kidins220 promotes or inhibits TCR signaling depending on the developmental context. summary statementWe demonstrate that the transmembrane scaffold protein Kidins220 switches its role twice in iNKT cell biology: from a positive to a negative regulator of TCR signal strength during thymic development and back to a positive regulator in the periphery.

immunology↗

bioRxiv2022

Breast cancer stem cell-derived tumors escape from γδ T cell immunosurveillance in vivo by modulating γδ T cell ligands

Triple negative breast cancer (TNBC) lacks targeted therapy options. TNBC is enriched in breast cancer stem cells (BCSCs), which play a key role in metastasis, chemoresistance, relapse and mortality. {gamma}{delta} T cells hold great potential in immunotherapy against cancer, and might be an alternative to target TNBC. {gamma}{delta} T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor sensing, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. We show that patient-derived triple negative BCSCs are efficiently recognized and killed by ex vivo expanded {gamma}{delta} T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to {gamma}{delta} T cell immunotherapy. Mechanistically, we unraveled concerted differentiation and immune escape: xenografted BCSCs lost stemness, expression of {gamma}{delta} T cell ligands, adhesion molecules and pAgs, thereby evading immune recognition by {gamma}{delta} T cells. Indeed, neither pro-migratory engineered {gamma}{delta} T cells, nor anti-PD-1 checkpoint blockade significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the {gamma}{delta} T cells, and could be pharmacologically reverted by Zoledronate or IFN- treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.

immunology↗

bioRxiv2022

Kidins220 regulates the development of B cells bearing the {lambda} light chain

The ratio between Ig{kappa} and Ig{lambda} light chain (LC)-expressing B cells varies considerably between species. We recently identified Kinase D-interacting substrate of 220 kDa (Kidins220) as an interaction partner of the BCR. In vivo ablation of Kidins220 in B cells resulted in a marked reduction of {lambda}LC-expressing B cells. Kidins220 knockout B cells fail to open and recombine the genes of the{lambda} LC locus, even in genetic scenarios where the{kappa} LC genes cannot be rearranged or where the {kappa}LC confers autoreactivity.{kappa} LC gene recombination and expression in Kidins220-deficient B cells is normal. Kidins220 regulates the development of {lambda}LC B cells by enhancing the survival of developing B cells and thereby extending the time-window in which the{lambda} LC locus opens and the genes are rearranged and transcribed. Further, our data suggest that Kidins220 guarantees optimal pre-BCR and BCR signaling to induce{lambda} LC locus opening and gene recombination during B cell development and receptor editing. One Sentence SummaryWe demonstrate that the scaffold protein Kidins220 regulates the development of {lambda}LC B cells by supporting B cell precursor survival and optimizing pre-BCR and BCR signaling to open, recombine, and transcribe the genes of the{lambda} LC locus.

immunology↗