4.6 Article

Studies of Lymphocyte Reconstitution in a Humanized Mouse Model Reveal a Requirement of T Cells for Human B Cell Maturation

Journal

JOURNAL OF IMMUNOLOGY
Volume 190, Issue 5, Pages 2090-2101

Publisher

AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1202810

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Funding

  1. National Institutes of Health [R21-AI073629]
  2. Arthritis Foundation Innovative Research Grant
  3. National Jewish Health Translational Research Initiative Grant
  4. Department of Defense [W81AWH-07-01-0550]

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The hematopoietic humanized mouse (hu-mouse) model is a powerful resource to study and manipulate the human immune system. However, a major and recurrent issue with this model has been the poor maturation of B cells that fail to progress beyond the transitional B cell stage. Of interest, a similar problem has been reported in transplant patients who receive cord blood stem cells. In this study, we characterize the development of human B and T cells in the lymph nodes (LNs) and spleen of BALB/c-Rag2(null) Il2r gamma(null) hu-mice. We find a dominant population of immature B cells in the blood and spleen early, followed by a population of human T cells, coincident with the detection of LNs. Notably, in older mice we observe a major population of mature B cells in LNs and in the spleens of mice with higher T cell frequencies. Moreover, we demonstrate that T cells are necessary for B cell maturation, as introduction of autologous human T cells expedites the appearance of mature B cells, whereas in vivo depletion of T cells retards B cell maturation. The presence of the mature B cell population correlates with enhanced IgG and Ag-specific responses to both T cell-dependent and T cell-independent challenges, indicating their functionality. These findings enhance our understanding of human B cell development, provide increased details of the reconstitution dynamics of hu-mice, and validate the use of this animal model to study mechanisms and treatments for the similar delay of functional B cells associated with cord blood transplantations. The Journal of Immunology, 2013, 190: 2090-2101.

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