Lymph node formation and B cell homeostasis require IKK-α in distinct endothelial cell-derived compartments

Area of Science:

• Immunology
• Developmental Biology
• Cell Biology

Background:

• IκB kinase (IKK)-α signaling is crucial for noncanonical NF-κB activation.
• Global IKK-α inactivation leads to defective lymph node (LN) formation and B cell maturation.
• IKK-α is expressed in vascular endothelial cells (ECs), but its specific role in ECs is unclear.

Purpose of the Study:

• To investigate the role of endothelial cell (EC)-intrinsic IKK-α in lymph node (LN) development and B cell homeostasis.
• To determine the specific contribution of IKK-α in different EC subtypes, including lymphatic ECs (LECs), to LN formation.

Main Methods:

• Generated conditional knockout mice (Ikkα mice) by crossing Ikkα mice with Tie2-cre or Cdh5-cre lines to ablate IKK-α in ECs.
• Created Ikkα mice lacking IKK-α specifically in hematopoietic cells (HCs).
• Generated Ikkα mice lacking IKK-α in lymphatic endothelial cells (LECs) to assess its role in lymphatic development.

Main Results:

• Global IKK-α inactivation in ECs recapitulated defects in LN formation and B cell maturation.
• Loss of IKK-α in HCs reduced mature B cell numbers but did not affect LN formation.
• Ablation of IKK-α in LECs resulted in complete absence of LNs, despite normal B cell numbers.

Conclusions:

• IKK-α in distinct EC-derived compartments plays unique roles in B cell homeostasis and LN development.
• Intrinsic IKK-α in lymphatic endothelial cells is indispensable for lymph node formation.
• Noncanonical NF-κB signaling via IKK-α in LECs is critical for establishing the structural foundation of lymph nodes.