Immunomodulation of delayed-type hypersensitivity responses by mesenchymal stem cells is associated with bystander T cell apoptosis in the draining lymph node.
Disease amelioration by mesenchymal stem cells (MSCs) has been shown to be closely related to their immunomodulatory functions on the host immune system in many disease models. However, the underlying mechanisms of how these cells affect the immune cells in vivo are not fully understood. In this study, we report findings that a small but significant number of MSCs accumulate in the secondary lymphoid organs and attenuate delayed-type hypersensitivity (DTH) response by inducing apoptotic cell death of surrounding immune cells in the draining lymph node (LN). In the migration study, i.v. infused GFP-MSCs preferentially accumulated at the boundary between the paracortical area and the germinal center in the LNs, in close proximity to various types of immune cells including T, B, and dendritic cells in a dose-dependent manner. As a result, accumulated MSCs markedly attenuated DTH response in proportion to the number of MSCs infused. During the DTH response, the infiltration of T cells in the challenged site was significantly decreased, whereas a number of apoptotic T cells were remarkably increased in the draining LN. Apoptosis was significantly induced in activated T cells (CD3(+) and BrdU(+)), but not in the resting T cells (CD3(+) and BrdU(-)). NO was associated with these apoptotic events. Taken together, we conclude that significant numbers of i.v. infused MSCs preferentially localize in the draining LN, where they induce apoptosis of the activated T cells by producing NO and thus attenuate the DTH response.
Lim
Jong-Hyung
JH
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea.
Kim
Jung-Sik
JS
Yoon
Il-Hee
IH
Shin
Jun-Seop
JS
Nam
Hye-Young
HY
Yang
Seung-Ha
SH
Kim
Sang-Joon
SJ
Park
Chung-Gyu
CG
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D024201:Bystander Effect / Q000276:immunology; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006968:Hypersensitivity, Delayed / Q000276:immunology* / Q000378:metabolism; D056747:Immunomodulation / Q000276:immunology*; D020287:In Situ Nick-End Labeling; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
D009569:Nitric Oxide