TY - JOUR
T1 - A dose effect of IL-7 on thymocyte development
AU - El Kassar, Nahed
AU - Lucas, Philip J.
AU - Klug, David B.
AU - Zamisch, Monica
AU - Merchant, Melinda
AU - Bare, Catherine V.
AU - Choudhury, Baishakhi
AU - Sharrow, Susan O.
AU - Richie, Ellen
AU - Mackall, Crystal L.
AU - Gress, Ronald E.
PY - 2004/9/1
Y1 - 2004/9/1
N2 - To study interleukin-7 (IL-7) in early thymocyte development, we generated mice transgenic (Tg) for the IL-7 gene under control of the lck proximal promoter. Founder line TgA, with the lowest level of IL-7 overexpression, showed enhanced αβ T-cell development. In contrast, in the highest overexpressing founder line, TgB, αβ T-cell development was disturbed with a block at the earliest intrathymic precursor stage. This was due to decreased progenitor proliferation as assessed by Ki-67 staining and in vivo bromodeoxyuridine (BrdU) incorporation. Bcl-2 was up-regulated in T-cell-committed progenitors in all Tg lines, and accounted for greater numbers of double positive (DP), CD4 single positive (SP), and CD8SP thymocytes in TgA mice where, in contrast to TgB mice, thymocyte progenitor proliferation was normal. Mixed marrow chimeras using TgB+ and congenic mice as donors, and experiments using anti-IL-7 monoclonal antibody (MAb) in vivo, confirmed the role of IL-7 protein in the observed TgB phenotype. In conclusion, at low Tg overexpression, IL-7 enhanced αβ T-cell development by increasing thymocyte progenitor survival, while at high overexpression IL-7 reduces their proliferation, inducing a dramatic block in DP production. These results show for the first time in vivo a dose effect of IL-7 on αβ T-cell development and have implications for IL-7 in the clinical setting.
AB - To study interleukin-7 (IL-7) in early thymocyte development, we generated mice transgenic (Tg) for the IL-7 gene under control of the lck proximal promoter. Founder line TgA, with the lowest level of IL-7 overexpression, showed enhanced αβ T-cell development. In contrast, in the highest overexpressing founder line, TgB, αβ T-cell development was disturbed with a block at the earliest intrathymic precursor stage. This was due to decreased progenitor proliferation as assessed by Ki-67 staining and in vivo bromodeoxyuridine (BrdU) incorporation. Bcl-2 was up-regulated in T-cell-committed progenitors in all Tg lines, and accounted for greater numbers of double positive (DP), CD4 single positive (SP), and CD8SP thymocytes in TgA mice where, in contrast to TgB mice, thymocyte progenitor proliferation was normal. Mixed marrow chimeras using TgB+ and congenic mice as donors, and experiments using anti-IL-7 monoclonal antibody (MAb) in vivo, confirmed the role of IL-7 protein in the observed TgB phenotype. In conclusion, at low Tg overexpression, IL-7 enhanced αβ T-cell development by increasing thymocyte progenitor survival, while at high overexpression IL-7 reduces their proliferation, inducing a dramatic block in DP production. These results show for the first time in vivo a dose effect of IL-7 on αβ T-cell development and have implications for IL-7 in the clinical setting.
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U2 - 10.1182/blood-2004-01-0201
DO - 10.1182/blood-2004-01-0201
M3 - Article
C2 - 15155461
AN - SCOPUS:4444284575
SN - 0006-4971
VL - 104
SP - 1419
EP - 1427
JO - Blood
JF - Blood
IS - 5
ER -