Project description:Human RLTPR deficiency is a combined immunodeficiency affecting the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells. This SubSeries contains high throughput gene expression data from primary CD4+ T cells of patients with RLTPR deficiency and controls.
Project description:Dysregulation of DNA double-strand break (DSB) repair leads to adaptive immunodeficiency, while the remaining lymphocytes are aberrantly activated and provoke inflammation. To clarify the biological impact of the LIG4 W447C variant identified in our patient, we generated the mutant mice of DNA ligase IV (LIG4), which is critical for DSB repair. Lig4_W447C/W447C mice showed severe intestinal inflammation under adaptive immunodeficiency. The inflammation was featured by a marked infiltration of T helper type 1 (Th1) cells and macrophages. We used scRNA-seq to analyse the detailed splenocyte population and T cell receptor repertoire in Lig4_W447C/W447C mice. Evaluation of the T cell receptor repertoire in Lig4_W447C/W447C mice revealed activated oligoclonal Th1 cells with restricted Vα diversity. Thus, our present results with our novel hypomorphic Lig4 mutant mice show that defective DSB repair leads to Th1-dependent intestinal inflammation under severe adaptive immunodeficiency.
Project description:Major Histocompatibility Complex (MHC) class II (MHCII) deficiency, also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. The contribution of thymic epithelial cell (TEC) defects to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC alterations in this disease. We observed an overall perturbation of thymic structure and function in both MHCII-/- mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, in MHCII-/- mice, impaired cross-talk and mTEC maturation resulted in altered promiscuous gene expression and leaky central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential effect of hematopoietic stem cell transplantation in MHCII deficiency.