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Expression of CTLA‐4 and FOXP3 in cis protects from lethal lymphoproliferative disease
Author(s) -
Chikuma Shunsuke,
Bluestone Jeffrey A.
Publication year - 2007
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.200737159
Subject(s) - ctla 4 , foxp3 , biology , immunology , t cell , autoimmunity , t lymphocyte , autoimmune disease , bone marrow , regulatory t cell , antibody , immune system , il 2 receptor
Abstract Both CTLA‐4‐deficient and FoxP3‐deficient mice exhibit a short life span due to massive lymphoproliferation (LP) and a systemic autoimmune‐like syndrome. Although it has been postulated that both diseases result from regulatory T cell (T reg ) defects, there have been no direct complementation studies to elucidate their relationship in homeostatic lymphocyte proliferation during the neonatal period. In this study, reconstitution of sublethally irradiated RAG KO mice with either CTLA‐4‐deficient or FoxP3‐deficient bone marrow (BM) resulted in LP disease similar to that observed in CTLA‐4 KO or Scurfy mice, respectively. Although co‐injection of BM from wild‐type mice inhibited the activation of CTLA‐4‐deficient or FoxP3‐deficient T cells and ameliorated LP disease through extrinsic regulatory mechanisms by T reg cells, mice that had received the BM mixture of Scurfy and CTLA‐4 KO BM eventually died of incomplete protection. These results suggest common attributes of both diseases, but expression of both CTLA‐4 and FoxP3 on the same cell subset is essential to fully prevent LP disease.