Leptin Receptor Deficiency fi ciency Impairs Lymph Node Development and Adaptive Immune Response

Activation and clonal expansion of the Ag-specific adaptive immune response in the draining lymph node is essential to clearing influenza A virus infections. Activation sufficient for virus clearance is dependent on the lymph node's ' s architectural organization that is maintained by stromal cells, chiefly fibroblastic reticular cells. During an analysis of influenza A virus clearance in leptin receptor knockout (DB/DB) mice, we observed that the DB/DB mice have markedly reduced numbers of lymph node fibroblastic reticular cells at the steady state. The reduction in lymph node fibroblastic reticular cells resulted in abnormal lymph node organization and diminished numbers of adaptive immune cells in the lymph nodes under homeostatic conditions. As a consequence, the DB/DB mice were impaired in their ability to generate an effective influenza-specific adaptive immune response, which prevented virus clearance. Using leptin receptor mutant mice with point mutations at distinct signaling sites in the leptin receptor, we were able to link the leptin receptor's ' s signaling domain tyrosine 985, which does not contribute to obesity, to lymph node fibroblastic reticular cell development and function. These results demonstrate a novel role for leptin receptor signaling in regulating lymph node development in a manner that is crucial to the generation of Ag-specific adaptive immune responses. The Journal of Immunology, 2024, 212: 974-981.- 981.