Natural Th17 cells are critically regulated by functional medullary thymic microenvironments

Area of Science:

• Immunology
• Cell Biology
• Developmental Biology

Background:

• The thymic medulla is crucial for central T-cell tolerance and the maturation of various natural αβT-cell subsets.
• Natural IL-17-secreting CD4(+)αβT-cells (nTh17) are a recently identified subset that matures intrathymically, with unclear regulatory mechanisms.
• Dysregulation of nTh17 responses may contribute to inflammatory conditions.

Purpose of the Study:

• To investigate the intrathymic mechanisms regulating the development of natural αβT-cell subsets, particularly nTh17 cells.
• To identify key molecular and cellular components within the thymic medulla essential for nTh17 development.

Main Methods:

• Comparative analysis of distinct natural αβT-cell development in the thymus.
• Assessment of the roles of thymic stromal MHC class II, RelB-dependent medullary thymic epithelial cells (mTEC), and Aire(+) mTEC in nTh17 development.
• Evaluation of the requirement for ICOS-ligand and CD80/86 costimulation, including expression by thymic epithelial cells.
• Investigation of inducible nitric oxide synthase (iNOS) function in nTh17 regulation.

Main Results:

• Thymic stromal MHC class II expression and RelB-dependent mTEC, including Aire(+) mTEC, are essential for nTh17 development.
• nTh17 development shows a partial, non-redundant requirement for ICOS-ligand and CD80/86 costimulation.
• CD80/86 expression by thymic epithelial cells is dispensable for nTh17 development.
• Inducible nitric oxide synthase (iNOS) in mTEC is not essential for constraining thymic nTh17 development.

Conclusions:

• The thymic medulla plays a critical role in the differential regulation of novel natural αβT-cell subsets like nTh17.
• These findings uncover additional regulatory mechanisms within the thymic medulla governing T-cell responses relevant to autoimmunity and inflammation.