Conserved and divergent aspects of human T-cell development and migration in humanized mice.
Humanized mice represent an important model to study the development and function of the human immune system. While it is known that mouse thymic stromal cells can support human T-cell development, the extent of interspecies cross-talk and the degree to which these systems recapitulate normal human T-cell development remain unclear. To address these questions, we compared conventional and non-conventional T-cell development in a neonatal chimera humanized mouse model with that seen in human fetal and neonatal thymus samples, and also examined the impact of a human HLA-A2 transgene expressed by the mouse stroma. Given that dynamic migration and cell-cell interactions are essential for T-cell differentiation, we also studied the intrathymic migration pattern of human thymocytes developing in a murine thymic environment. We found that both conventional T-cell development and intra-thymic migration patterns in humanized mice closely resemble human thymopoiesis. Additionally, we show that developing human thymocytes engage in short, serial interactions with other human hematopoietic-derived cells. However, non-conventional T-cell differentiation in humanized mice differed from both fetal and neonatal human thymopoiesis, including a marked deficiency of Foxp3(+) T-cell development. These data suggest that although the murine thymic microenvironment can support a number of aspects of human T-cell development, important differences remain, and additional human-specific factors may be required.
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, UC Berkeley, Berkeley, CA, USA.|Division of Neonatology, Department of Pediatrics, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.
Joanna
J
Halkias
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, UC Berkeley, Berkeley, CA, USA.
Bonnie
B
Yen
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, UC Berkeley, Berkeley, CA, USA.
Kayleigh T
KT
Taylor
Division of Cardiothoracic Surgery, Department of Pediatrics, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.|Division of Pediatric Cardiac Surgery, Department of Cardiothoracic Surgery, Lucile Packard Children's Hospital/Stanford University, Palo Alto, CA, USA.
Olaf
O
Reinhartz
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, UC Berkeley, Berkeley, CA, USA.
Astar
A
Winoto
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, UC Berkeley, Berkeley, CA, USA.
Ellen A
EA
Robey
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, UC Berkeley, Berkeley, CA, USA.
Heather J
HJ
Melichar
D000818:Animals; D015415:Biomarkers; D002450:Cell Communication; D002454:Cell Differentiation; D002465:Cell Movement; D060833:Cellular Microenvironment; D015870:Gene Expression; D017930:Genes, Reporter; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000166:cytology / Q000502:physiology; D038041:Lymphopoiesis; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D038081:Organogenesis; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D060168:Thymocytes / Q000166:cytology / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology / Q000502:physiology
D015415:Biomarkers; D015789:HLA-A2 Antigen