CD4+CD25+ regulatory T cells resist a novel form of CD28- and Fas-dependent p53-induced T cell apoptosis

Nagendra Singh, Mutsumi Yamamoto, Mariko Takami, Yoichi Seki, Mayuko Takezaki, Andrew L. Mellor, Makio Iwashima

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Ag receptor stimulation of preactivated T cells causes rapid cell death in an IL-2- and Fas-dependent manner. This phenomenon, known as activation-induced cell death (AICD), plays a pivotal role in the removal of Ag-reactive T cells after initial expansion. In this study, we report a novel form of T cell apoptosis that is distinct from classic AICD. When peripheral T cells were activated with anti-CD3 and anti-CD28 Abs precoated onto plastic plates, CD4+CD25- and CD8 T cells initially expanded but underwent massive apoptosis after 4 d. Unlike classic AICD, this type of T cell apoptosis pathway requires engagement of CD28 and expression of p53, a tumor-suppressor gene. The most striking feature of this form of apoptosis was regulatory T cell resistance. Under the same stimulating conditions, CD4+CD25 + T cells grew continuously beyond 4 d. Consequently, when the entire CD4 population was cultured with plate-bound anti-CD3 plus anti-CD28 Ab, CD4+CD25+FoxP3+ regulatory T cells outgrew nonregulatory T cells and expanded >7000-fold after 11 d. The data presented herein demonstrate a novel process of Ag-induced T cell death by sustained TCR and CD28 engagement and represent a simple and efficient procedure for the expansion of regulatory T cells in vitro.

Original languageEnglish (US)
Pages (from-to)94-104
Number of pages11
JournalJournal of Immunology
Issue number1
StatePublished - Jan 1 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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