MiR-205 Supports Thymopoiesis Following Stress by Positively Regulating Foxn1 Expression

Abstract

Abstract T cells are a critical component of the adaptive immune system, developing within the thymus. Immature thymocytes interact with an interconnected meshwork of thymic epithelial cells (TECs) to establish the T cell repertoire. The developmental process is extremely stress sensitive, as the thymus can undergo a rapid involution in response to diverse inflammatory conditions, and a more prolonged hypoplasia during aging. The type of stress predicates whether TECs, thymocytes, and/or myeloid cell populations are affected. Several microRNAs (miRs) have been identified in the thymus based on their ability to mitigate the stress damage. We identified miR-205 as a stress responsive miR specifically expressed in TECs. Mice generated with a conditional ablation of miR-205 in TECs exhibit an age and sex-dependent thymic hypoplasia beginning at 8 weeks. Under stress conditions involving a type I interferon response (dsRNA mimic; polyI:C), the TEC-miR-205 deficient mice had a severe thymic atrophy compared to littermate controls. The TEC-miR-205 deficient mice displayed a delayed recovery of single positive CD4 and CD8 thymocytes, likely resulting from a block in the cortical TEC expansion. qPCR and gene expression comparisons revealed that the miR-205 deficient TECs had significant changes in chemokine/chemokine receptor and antigen processing pathways. MiR-205 positively regulated Foxn1 transcription factor expression, the master regulator of TEC development and function. Interestingly, miR-205 is encoded within a long non-coding RNA (lncRNA), 4631405K08Rik. Current experiments will reveal the mechanisms by which the miR and lncRNA are transcriptionally regulated, and how these affect Foxn1 expression to support thymopoiesis.