BackgroundHumanized mice able to reconstitute a surrogate human immune system (HIS) can be used for studies on human immunology and may provide a predictive preclinical model for human vaccines prior to clinical trials. However, current humanized mouse models show sub-optimal human T cell reconstitution and limited ability to support immunoglobulin class switching by human B cells. This limitation has been attributed to the lack of expression of Human Leukocyte Antigens (HLA) molecules in mouse lymphoid organs. Recently, humanized mice expressing HLA class I molecules have been generated but showed little improvement in human T cell reconstitution and function of T and B cells.MethodsWe have generated NOD.Rag1KO.IL2RγcKO mice expressing HLA class II (HLA-DR4) molecules under the I-Ed promoter that were infused as adults with HLA-DR-matched human hematopoietic stem cells (HSC). Littermates lacking expression of HLA-DR4 molecules were used as control.ResultsHSC-infused HLA-DR4.NOD.Rag1KO.IL-2RγcKO mice developed a very high reconstitution rate (>90%) with long-lived and functional human T and B cells. Unlike previous humanized mouse models reported in the literature and our control mice, the HLA-DR4 expressing mice reconstituted serum levels (natural antibodies) of human IgM, IgG (all four subclasses), IgA, and IgE comparable to humans, and elicited high titers of specific human IgG antibodies upon tetanus toxoid vaccination.ConclusionsOur study demonstrates the critical role of HLA class II molecules for development of functional human T cells able to support immunoglobulin class switching and efficiently respond to vaccination.

Mitochondria are dynamic organelles that undergo fusion and fission events. Mitochondrial dynamics are required for mitochondrial viability and for responses to changes in bioenergetic status. Here we describe an insulin-signaling and SCFLIN-23-regulated pathway that controls mitochondrial fusion in Caenorhabditis elegans by repressing the expression of the mitochondrial proteases SPG-7 and PPGN-1. This pathway is required for mitochondrial fusion in response to physical exertion, and for the associated extension in lifespan. We show that diverse longevity pathways exhibit increased levels of elongated mitochondria. The increased mitochondrial fusion is essential for longevity in the diverse longevity pathways, as inhibiting mitochondrial fusion reduces their lifespans to wild-type levels. Our results suggest that increased mitochondrial fusion is not a major driver of longevity, but rather is essential to allow the survival of older animals beyond their normal lifespan in diverse longevity pathways.

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