Deletion of DOCK2, a regulator of the actin cytoskeleton in lymphocytes, suppresses cardiac allograft rejection.
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-gamma, 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.
Jiang
Hongsi
H
Astellas Research Institute of America, Inc., Evanston, IL, USA.
Pan
Fan
F
Erickson
Laurie M
LM
Jang
Mei-Shiang
MS
Sanui
Terukazu
T
Kunisaki
Yuya
Y
Sasazuki
Takehiko
T
Kobayashi
Masakazu
M
Fukui
Yoshinori
Y
D000199:Actins / Q000378:metabolism*; D000818:Animals; D003599:Cytoskeleton / Q000276:immunology / Q000378:metabolism*; D003601:Cytotoxicity Tests, Immunologic; D017931:DNA Primers; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017353:Gene Deletion; D006084:Graft Rejection / Q000276:immunology*; D020662:Guanine Nucleotide Exchange Factors; D016027:Heart Transplantation / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D023001:Transplantation Tolerance / Q000276:immunology*
D000199:Actins; D017931:DNA Primers; C471356:DOCK2 protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D018398:Homeodomain Proteins; C064658:RAG-1 protein