TSLP plays roles that are distinct from IL7 in normal human B cell development (HEM1P.227)

The role of TSLP in human B cell development is largely unknown and its function in context of IL7 is unstudied. We found that TSLP can replace IL7 in providing a signal essential for in vitro production and proliferation of human CD19+ Pax-5+ B cell progenitors. To study the role of TSLP in human B cell development, in the context of IL7 stimulation, we developed a novel xenograft model. Mouse IL7 is active on human cells, however, this is not the case for TSLP. We took advantage of this to develop a xenograft model system comprised of mice that provide human TSLP (+T mice) and control mice that do not (-T mice). Using this model we found that TSLP increases proliferation and upregulates Mcl-1 in CD34+CD19-IL7Ra progenitors resulting in a 3-4 fold expansion of the CD34+ pro-B cell compartment in +T as compared to -T mice. This expansion is maintained during subsequent stages of B cell development, partially due to increased protection from apoptosis that occurs independently of Bcl-2 family pro-survival proteins. While TSLP stimulates in vitro proliferation of pro-B cells, in vivo proliferation of B lineage precursors was similar in +T and -T mice suggesting redundancy with IL7. B cell subsets in normal pediatric bone marrow samples show progenitor ratios and Mcl-1 expression that mirrors that in +T xenograft mice. These data provide evidence that TSLP function in human B cell development includes both unique activities as well as activities redundant to those of IL7.