Expression of HLA Class II Molecules in Humanized NOD.Rag1KO.IL2RgcKO Mice is Critical for Development and Function of Human T and B Cells
NAVAL MEDICAL RESEARCH CENTER SILVER SPRING MD
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Background Humanized 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. Methods We have generated NOD.Rag1KO.IL2RccKO 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. Results HSC-infused HLA-DR4.NOD.Rag1KO.IL-2RccKO mice developed a very high reconstitution rate .90 with longlived 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. Conclusions Our 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.
- Medicine and Medical Research