A new Treg-specific, FoxP3-GFP-hCre BAC transgenic was crossed to a conditional Dicer knock-out mouse strain to analyze the role of microRNAs (miRNA) in the development and function of regulatory T cells (Tregs). Although thymic Tregs developed normally in this setting, the cells showed evidence of altered differentiation and dysfunction in the periphery. Dicer-deficient Treg lineage cells failed to remain stable as a subset of cells down-regulated the Treg-specific transcription factor, FoxP3, while the majority expressed altered levels of multiple genes and proteins (including Neuropilin 1, GITR and CTLA-4) associated with the Treg fingerprint. In fact, a significant percentage of the Treg lineage cells took on a Th memory phenotype including increased levels of CD127, IL-4, and interferon-g. Importantly, Dicer-deficient Tregs lost suppression activity in vivo; the mice rapidly developed fatal systemic autoimmune disease resembling the FoxP3 knockout phenotype. These results support a central role for miRNAs in maintaining the stability of differentiated Treg function in vivo and homeostasis of the adaptive immune system.
Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity.
No sample metadata fields
View SamplesImmunosurveillance of secondary lymphoid organs (SLO) is performed by central memory T cells that recirculate through blood. Resident memory T cells (TRM) remain parked in nonlymphoid tissues and often stably express CD69. We recently identified TRM within SLO, and this study addresses knowledge gaps in their origin and phenotype. Parabiosis of dirty mice revealed that CD69 expression is insufficient to infer stable residence. Using selective depletion strategies, parabiosis, imaging, tissue grafting, and photoactivatable T cells, we report that restimulation of TRM within the skin or mucosa results in a substantial increase in TRM that patrol all regions of draining lymph nodes. SLO TRM were derived from nonlymphoid tissue residents. Transcriptional profiling and flow cytometry revealed a refined phenotype shared between both nonlymphoid and SLO TRM. These data demonstrate the nonlymphoid origin of SLO TRM and suggest vaccination strategies by which memory CD8 T cell immunosurveillance can be regionalized to specific lymph nodes.
T Cells in Nonlymphoid Tissues Give Rise to Lymph-Node-Resident Memory T Cells.
Specimen part
View SamplesThe goal was to identify genes that are differentially expressed between the bone marrow-derived CD11b+ myeloid cells infiltrating intracranial tumors and the peripheral myeloid cells (e.g. infiltrating the spleen and bone marrow).
Hematopoietic Stem Cell Gene Therapy for Brain Metastases Using Myeloid Cell-Specific Gene Promoters.
Age, Specimen part
View Samples