PT - JOURNAL ARTICLE AU - Chan-Su Park AU - Jian Guan AU - Peter Rhee AU - Federico Gonzalez AU - Laurent Coscoy AU - Ellen A. Robey AU - Nilabh Shastri AU - Scheherazade Sadegh-Nasseri TI - Fam49b dampens TCR signal strength to regulate survival of positively selected thymocytes AID - 10.1101/2022.01.18.476719 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.01.18.476719 4099 - http://biorxiv.org/content/early/2022/01/18/2022.01.18.476719.short 4100 - http://biorxiv.org/content/early/2022/01/18/2022.01.18.476719.full AB - The fate of developing T cells is determined by the strength of T cell receptor (TCR) signal they receive in the thymus. This process is finely regulated through tuning of positive and negative regulators in thymocytes. The Family with sequence similarity 49 member B (Fam49b) protein is a newly discovered negative regulator of TCR signaling that has been shown to suppress Rac-1 activity in vitro in cultured T cell lines. However, the contribution of Fam49b to thymic development of T cells is unknown. To investigate this important issue, we generated a novel mouse line deficient in Fam49b (Fam49b-KO). We observed that Fam49b-KO double positive (DP) thymocytes underwent excessive negative selection, whereas the positive selection stage was unaffected. This altered development process resulted in significant reductions in CD4 and CD8 single positive thymocytes as well as peripheral T cells. Interestingly, a large proportion of the TCRγδ+ and CD8αα+TCRαβ+ gut intraepithelial T lymphocytes were absent in Fam49b-KO mice. Our results demonstrate that Fam49b dampens thymocytes TCR signaling in order to escape negative selection during development, uncovering the function of Fam49b as a critical regulator of selection process to ensure normal thymocyte development.Competing Interest StatementThe authors have declared no competing interest.TCRT cell receptorFam49aFamily with sequence similarity 49 member AFam49bFamily with sequence similarity 49 member BDNdouble negativeDPdouble positiveSPsingle positiveRho-GTPasesRho family of small guanosine triphosphatasesGEFsguanine nucleotide exchange factorsGAPsGTPase-activating proteinsIELsintraepithelial lymphocytesTregcells Regulatory T celliNKT cellsinvariant natural killer T cellsAPCsantigen presenting cells