The Role of Interleukin-7 in the Regulation of Normal Human B Lymphopoiesis

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ProQuest, 2008 - 257 pages
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The role of IL-7 in murine lymphoid development has been extensively documented, but the role in human B cell development remains unclear. Studies of human blood cell development have been facilitated by the use of in vitro stromal cell co-cultures. One murine stromal cell line, MS-5, was previously used to support human lymphohematopoiesis from cord blood CD34+ hematopoietic progenitors. The initial goal of this thesis was to identify the cytokines synthesized by MS-5 that support human B cell development. When cord blood CD34+ hematopoietic progenitors were plated on MS-5, a population of CD19+ pro-B cells developed of which ∼30% expressed the IL-7R (CD127). Murine IL-7 was detected in MS-5 supernatants and demonstrated to be biologically active for human CD19+ pro-B cells. Limiting the biological activity of mIL-7 inhibited the development of CD19+ cells in this model. However, IL-7 by itself could not promote proliferation. Although the complete identity of the MS-5 gene products that cooperate with IL-7 was not resolved, insulin-like growth factor 1 may play at least a partial role. The functional consequence of CD127 expression on human B-lineage cells was examined by two approaches. The first compared IL-7 signaling in human CD34+ thymocytes and CD19+ B-lineage cells. These two populations exhibited similarities in activation of STAT5 and ERK1/2, but differences in activation of the PI3K/AKT pathway. The second compared the survival, Ig gene rearrangement and protein expression characteristics of FACS-purified CD19+/CD127+ and CD19+/CD127- cells. CD19+/CD127+ cells from CD34+ cell/MS-5 cultures had enhanced survival capacity, DJH but few VDJH rearrangements, and essentially no IgL rearrangements. In contrast, CD19+/CD127- cells exhibited poor survival characteristics, similar IgH rearrangements, but extensive rearrangement at the IgL loci. These collective results indicate that IL-7 transduces a replicative signal to human B-lineage cells that is complemented by additional stromal cell-derived signals, and that signaling through CD127 is incompatible with the onset of IgL rearrangement. The xenogeneic model can now be used as a biological platform upon which future studies of the role of IL-7 and other cytokines in normal and abnormal (i.e., immune deficiencies and leukemia) human B cell development can be based.
  

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Contents

Sites of mammalian Bcell development 2
2
Literature Review References13
13
Characterization of the CD34+ cellMS5 xenogeneic
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Murine and human IL7 activate STAT5 and induce
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Stromal cell derived interleukin7 transduces a signal
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to human CD19+ Blineage cells that results in proliferation 100 Chapter 4 CD127 expression defines a population of CD19+ proB cells with enhance...
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IL7 activates the PI3KAKT pathway in normal
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References
224
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