RESUMO
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 alphabeta T-cell development. In contrast, in the highest overexpressing founder line, TgB, alphabeta 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 alphabeta 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 alphabeta T-cell development and have implications for IL-7 in the clinical setting.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento/imunologia , Interleucina-7/genética , Timo/embriologia , Timo/fisiologia , Animais , Linfócitos B/citologia , Linfócitos B/fisiologia , Divisão Celular/imunologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/fisiologia , Antígenos Comuns de Leucócito/metabolismo , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Células-Tronco/citologia , Células-Tronco/fisiologia , Linfócitos T/citologia , Linfócitos T/fisiologia , Timo/citologia , Regulação para Cima/imunologiaRESUMO
Thymic epithelial cells (TECs) in adult mice have been classified into distinct subsets based on keratin expression profiles. To explore the emergence of TEC subsets during ontogeny, we analyzed keratin 8 and keratin 5 expression at several stages of fetal development in normal C57BL/6J mice. In addition, thymic epithelial development and compartmentalization were explored in recombination-activating gene 2/common cytokine receptor gamma-chain-deficient and Ikaros-null mice that sustain early and profound blocks in thymocyte differentiation. The results demonstrate that initial patterning of the thymic epithelial compartment as defined by differential keratin expression does not depend on inductive signals from hematopoietic cells. However, thymocyte-derived signals are required during late fetal stages for continued development and maintenance of TEC subsets in the neonate and adult.