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Defective thymic progenitor development and mature T ‐cell responses in a mouse model for D own syndrome
Author(s) -
Lorenzo Laureanne P. E.,
Shatynski Kristen E.,
Clark Sarah,
Yarowsky Paul J.,
Williams Mark S.
Publication year - 2013
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12092
Subject(s) - thymic involution , thymocyte , biology , lymphopoiesis , progenitor cell , endocrinology , double negative , medicine , cytokine , t cell , spleen , haematopoiesis , immune system , receptor , involution (esoterism) , immunology , stem cell , microbiology and biotechnology , biochemistry , consciousness , neuroscience
Summary In addition to archetypal cognitive defects, D own syndrome ( DS ) is characterized by altered lymphocyte development and function, including premature thymic involution and increased incidence of infections. However, the potential mechanisms for these changes have not been fully elucidated. The current study used the T s65 D n mouse model of DS to assess deficiencies in T ‐cell development and possible molecular alterations. T s65 D n mice exhibited premature thymic involution and a threefold to fourfold decrease in the number and proportion of immature, double‐negative thymocyte progenitors. In addition, there were twofold fewer double‐positive and CD 4 single‐positive thymocytes in T s65 D n thymuses. Reflecting this deficient thymic function, there were fewer naive T cells in the spleen and polyclonal stimulation of peripheral T cells exhibited a marked reduction in proliferation, suggesting a senescent phenotype. In contrast, B ‐cell progenitors were unchanged in the bone marrow of T s65 D n mice, but in the spleen, there were decreased transitional and follicular B cells and these cells proliferated less upon antigen receptor stimulus but not in response to lipopolysaccharide. As a potential mechanism for diminished thymic function, immature thymocyte populations expressed diminished levels of the cytokine receptor interleukin‐7 R α, which was associated with decreased proliferation and increased apoptosis. Increased oxidative stress and inhibition of the N otch pathway were identified as possible mediators of decreased interleukin‐7 R α expression in T s65 D n mice. The data suggest that immature thymocyte defects underlie immune dysfunction in DS and that increased oxidative stress and reduced cytokine signalling may alter lymphocyte development in T s65 D n mice.