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Modulation of cell cycle progression by CTLA4‐CD80/CD86 interactions on CD4 + T cells depends on strength of the CD3 signal: critical role for IL‐2
Author(s) -
Mukherjee Sambuddho,
Ahmed Asma,
Malu Shruti,
Nandi Dipankar
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0505260
Subject(s) - cd80 , cd86 , biology , microbiology and biotechnology , cytotoxic t cell , cd3 , t cell , interleukin 2 , cd28 , cd40 , antigen , immunology , immune system , biochemistry , cd8 , in vitro
Cytotoxic T‐lymphocyte antigen 4 (CTLA4) is a well‐studied T cell costimulatory receptor that is known to inhibit T cell activation. In this study, the relationship between strength of the first signal and costimulatory interactions on primary mouse CD4 + T cells was investigated. CTLA4‐CD80/CD86 interactions differentially modulate T cell cycling based on the mode of CD3 signal: Activation with plate‐bound (pb) anti‐CD3 generates a strong signal compared with a weak signal with soluble (sol) anti‐CD3, resulting in approximately sevenfold higher amounts of interleukin (IL)‐2 and an increase in cell cycling. Activation of T cells with sol anti‐CD3 (weak signal) together with CTLA4‐CD80/CD86 blockade lowers IL‐2 production and cell cycling, demonstrating an enhancing role for these interactions. Conversely, blockade of CTLA4‐CD80/CD86 interactions on T cells activated with pb anti‐CD3 (strong signal) increases proliferation, which is consistent with CTLA4 as a negative regulator. Also, coculture of T cells with Chinese hamster ovary cells expressing CD80 or CD86 demonstrates that the strength of the primary signal plays an important role. It is important that modulation of IL‐2 amounts leads to distinct alterations in the functional effects of CTLA4‐CD80/CD86 interactions. On increasing IL‐2 amounts, activation of T cells stimulated with sol anti‐CD3 (weak signal) and CTLA4‐CD80/CD86 blockade is greater compared with control. Concurrently, neutralization of IL‐2 greatly reduces activation of T cells stimulated with pb anti‐CD3 (strong signal) and CTLA4‐CD80/CD86 blockade compared with control. These results underscore the importance of strength of first signal, CTLA4‐CD80/CD86 interactions, and IL‐2 amounts in modulating primary CD4 + T cell responses.