TSLP or IL-7 provide an IL-7Rα signal that is critical for human B lymphopoiesis.
Thymic stromal lymphopoietin (TSLP) and IL-7 are cytokines that signal via the IL-7 receptor alpha (IL-7Rα) to exert both overlapping and unique functions during early stages of mouse B-cell development. In human B lymphopoiesis, the requirement for IL-7Rα signaling is controversial and the roles of IL-7 and TSLP are less clear. Here, we evaluated human B-cell production using novel in vitro and xenograft models of human B-cell development that provide selective IL-7 and human TSLP (hTSLP) stimulation. We show that in vitro human B-cell production is almost completely blocked in the absence of IL-7Rα stimulation, and that either TSLP or IL-7 can provide a signal critical for the production and proliferation of human CD19(+) PAX5(+) pro-B cells. Analysis of primary human bone marrow stromal cells shows that they express both IL-7 and TSLP, providing an in vivo source of these cytokines. We further show that the in vivo production of human pro-B cells under the influence of mouse IL-7 in a xenograft scenario is reduced by anti-IL-7 neutralizing antibodies, and that this loss can be restored by hTSLP at physiological levels. These data establish the importance of IL-7Rα mediated signals for normal human B-cell production.
School of Medicine, Loma Linda University, Loma Linda, CA, USA.
Terry-Ann M
TA
Milford
School of Medicine, Loma Linda University, Loma Linda, CA, USA.
Ruijun J
RJ
Su
School of Medicine, Loma Linda University, Loma Linda, CA, USA.
Olivia L
OL
Francis
School of Medicine, Loma Linda University, Loma Linda, CA, USA.
Ineavely
I
Baez
School of Medicine, Loma Linda University, Loma Linda, CA, USA.
Shannalee R
SR
Martinez
School of Medicine, Loma Linda University, Loma Linda, CA, USA.
Jacqueline S
JS
Coats
School of Pharmacy, Loma Linda University, Loma Linda, CA, USA.
Abby J
AJ
Weldon
School of Medicine, Loma Linda University, Loma Linda, CA, USA.
Milcris N
MN
Calderon
School of Medicine, Loma Linda University, Loma Linda, CA, USA.
Michael C
MC
Nwosu
School of Medicine, Loma Linda University, Loma Linda, CA, USA.
Allen R
AR
Botimer
School of Medicine, Loma Linda University, Loma Linda, CA, USA.
Batul T
BT
Suterwala
School of Medicine, Loma Linda University, Loma Linda, CA, USA.
Xiao-Bing
XB
Zhang
School of Medicine, Loma Linda University, Loma Linda, CA, USA.
Christopher L
CL
Morris
School of Pharmacy, Loma Linda University, Loma Linda, CA, USA.
David J
DJ
Weldon
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Sinisa
S
Dovat
School of Medicine, Loma Linda University, Loma Linda, CA, USA. kpayne@llu.edu.
Kimberly J
KJ
Payne
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism* / Q000494:pharmacology; D038041:Lymphopoiesis / Q000187:drug effects / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D000094632:Thymic Stromal Lymphopoietin
Human B lymphopoiesis; IL-7; Pro-B cell; TSLP; Xenograft