Lymphocyte Development and Immunoreactivity in IL-2 Deficient Mice

Schimpl, Anneliese; Hünig, Thomas; Berberich, Lisa Maxi; Erb, Klaus J.; Elbe, Adelheid; Stingl, Georg; Sadlack, Benjamin; Schorle, Hubert; Horak, Ivan D.

doi:10.1007/978-3-642-51479-1_40

Cited by 3 publications

(3 citation statements)

References 16 publications

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“…As shown in Fig. 1 A, cellularity of spleens remained normal in athymic IL-2 -'-mice, whereas their euthymic littermates developed severe lymphadenopathy (not shown) and splenomegaly, as previously described (5,6) . Moreover, the loss of splenic B cells ( Fig .…”

Section: Resultssupporting

confidence: 80%

“…Unexpectedly, however, mainstream T cell development in mice with a disrupted IL-2 gene is normal (4), and after 3-4 wk of age, peripheral T cells are even increased in number and display an activated phenotype. This marks the onset of a lethal syndrome characterized by splenomegaly and lymphadenopathy, an early burst ofB cell activation followed by their virtual disappearance, T cell infiltration of the bone marrow, anemia, autoantibody production, and a severe colitis preceded by an infiltration of the gut epithelium with CD4 and CD8 ot/(3 T cells (5)(6)(7)(8) . Hyperactivation of T cells and development of autoimmunity have also been observed in mice lacking the IL-2R/3 chain (9), supporting the concept that IL-2Rmediated signals are required for the containment of T cell activation in vivo.…”

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confidence: 99%

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Immunopathology of interleukin (IL) 2-deficient mice: thymus dependence and suppression by thymus-dependent cells with an intact IL-2 gene.

Krämer

Schimpl

Hünig

1995

The Journal of Experimental Medicine

129

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SummaryIntedeukin (IL) 2-deficient mice develop a fatal immunopathology characterized by lymphadenopathy, splenomegaly, T cell infiltration of the bone marrow, loss of B cells, anemia, and inflammation of the gut. The thymus dependence of these disease symptoms was tested by introducing the IL-2 mutation into athymic mice. With the exception of an increase in CD8+ intrahepatic oLlp T cells, IL-2 deficiency had no detectable effect on leukocyte composition or health of athymic mice, indicating a key role for thymus-derived T cells in the initiation of disease and demonstrating that B cell development and survival are independent of IL-2. In adoptive transfer studies, lymph node and spleen cells from euthymic IL-2-deficient mice induced disease in athymic mice with an intact IL-2 gene, suggesting that thymus-independent IL-2-expressing cells are unable to control the development of immune pathology . Both IL-2+ and IL-2 -' -bone marrow cells repopulated the thymus and the peripheral T cell compartment of the recombination activator gene 2-deficient recipients, and chimeras that had received IL-2-deficient bone marrow developed immune pathology . Disease development was, however, fully or at least partially prevented when 30% ofthe bone marrow inoculum was derived from mice able to express IL-2. These results demonstrate that the IL-2 deficiency syndrome depends on the intrathymic differentiation ofT cells carrying the IL-2 mutation, and that the abnormal activation of IL-2-deficient lymphocytes can be controlled by thymus-derived but not thymusindependent lymphocytes .

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Section: Resultssupporting

confidence: 80%

mentioning

confidence: 99%

Immunopathology of interleukin (IL) 2-deficient mice: thymus dependence and suppression by thymus-dependent cells with an intact IL-2 gene.

Krämer

Schimpl

Hünig

1995

The Journal of Experimental Medicine

129

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“…Either scenario could be of relevance to the immunopathology that develops with age in IL-2-deficient mice. The unchecked lymphoproliferation (43,44) and massive inflammation of the colon along with the formation of autoantibodies (44) points to a malfunctioning of counterregulatory mechanisms in these animals. The abnormal phenotypic composition of IL-2R3 + thymocytes in IL-2-deficient animals, i.e., the increased production of CD4-CD8c~/3 + at the expense of CD4-8-cells may thus contribute to the development bf the lymphoproliferative syndrome of IL-2 -/-mice.…”

Section: Discussionmentioning

confidence: 99%

Induction of interleukin 2 receptor beta chain expression by self-recognition in the thymus.

Hanke

Mitnacht

Boyd

et al. 1994

The Journal of Experimental Medicine

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Summary 1-2% of adult mouse thymocytes express the T cell receptor ~/B (TCtL-oe/B) together with the interleukin (IL) 2P, g (p70), but not the o~ (p 55) chain. We show that the previously described ol/~/-TCR + CD4-8-and the partially overlapping Ly6C + thymocytes are contained within this subset. Most IL-2R~ + ol/B-TCR + cells have a mature and activated (heat stable antigen [HSA]-, thymic shared antigen 1 [TSA-1]-, CD44hig h, CD69 +) phenotype. Overrepresentation of V~8.2 in both CD4-8-and CD4 and/or CD8 + IL-2RB + thymocytes suggests that IL-2RB expression is induced by a TCR-mediated activation event. In mice transgenic for an H-2K bspecific TCR, IL-21~ + ceils were abundant under conditions of mainstream negative selection, i.e., in the presence of K b, but absent under conditions of mainstream positive selection or in a nonselecting environment. Together, these results show that in addition to clonal deletion, selfrecognition by immature thymoeytes leads to phenotypic maturation of a small subset of thymocytes expressing IL-2R~. IL-2-deficient mice contain normal numbers of IL-2R~ + oe/B-TCR + thymocytes, indicating that like mainstream T cell development, this minor pathway of positive selection does not depend on IL-2. However, in the absence of IL-2, the CD4/CD8 subset composition of IL-2RB + thymocytes is skewed towards CD4-8 +, mostly at the expense of CD4-8-. A possible relevance of this finding for the development of the immune pathology of IL-2-deficient mice is discussed.

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