Deletion of DOCK2, a regulator of the actin cytoskeleton in lymphocytes, suppresses cardiac allograft rejection

Hongsi Jiang, Fan Pan, Laurie M. Erickson, Mei Shiang Jang, Terukazu Sanui, Yuya Kunisaki, Takehiko Sasazuki, Masakazu Kobayashi, Yoshinori Fukui

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Allograft rejection is induced by graft tissue infiltration of alloreactive T cells that are activated mainly in secondary lymphoid organs of the host. DOCK2 plays a critical role in lymphocyte homing and immunological synapse formation by regulating the actin cytoskeleton, yet its role in the in vivo immune response remains unknown. We show here that DOCK2 deficiency enables long-term survival of cardiac allografts across a complete mismatch of the major histocompatibility complex molecules. In DOCK2-deficient mice, alloreactivity and allocytotoxicity were suppressed significantly even after in vivo priming with alloantigens, which resulted in reduced intragraft expression of effector molecules, such as interferon-γ, granzyme B, and perforin. This is mediated, at least in part, by preventing potentially alloreactive T cells from recruiting into secondary lymphoid organs. In addition, we found that DOCK2 is critical for CD28-mediated Rac activation and is required for the full activation of alloreactive T cells. Although DOCK2-deficient, alloreactive T cells were activated in vitro in the presence of exogenous interleukin-2, these T cells, when transferred adoptively, failed to infiltrate into the allografts that were transplanted into RAG1-deficient mice. Thus, DOCK2 deficiency attenuates allograft rejection by simultaneously suppressing multiple and key processes. We propose that DOCK2 could be a novel molecular target for controlling transplant rejection. JEM

Original languageEnglish
Pages (from-to)1121-1130
Number of pages10
JournalJournal of Experimental Medicine
Volume202
Issue number8
DOIs
Publication statusPublished - Oct 17 2005

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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