Pivotal role of dendritic cell-derived CXCL10 in the retention of T helper cell 1 lymphocytes in secondary lymph nodes.
Various immune diseases are considered to be regulated by the balance of T helper (Th)1 and Th2 subsets. Although Th lymphocytes are believed to be generated in draining lymph nodes (LNs), in vivo Th cell behaviors during Th1/Th2 polarization are largely unexplored. Using a murine granulomatous liver disease model induced by Propionibacterium acnes, we show that retention of Th1 cells in the LNs is controlled by a chemokine, CXCL10/interferon (IFN) inducible protein 10 produced by mature dendritic cells (DCs). Hepatic LN DCs preferentially produced CXCL10 to attract 5'-bromo-2'-deoxyuridine (BrdU)+CD4+ T cells and form clusters with IFN-gamma-producing CD4+ T cells by day 7 after antigen challenge. Blockade of CXCL10 dramatically altered the distribution of cluster-forming BrdU+CD4+ T cells. BrdU+CD4+ T cells in the hepatic LNs were selectively diminished while those in the circulation were significantly increased by treatment with anti-CXCL10 monoclonal antibody. This was accompanied by accelerated infiltration of memory T cells into the periphery of hepatic granuloma sites, most of them were in cell cycle and further produced higher amount of IFN-gamma leading to exacerbation of liver injury. Thus, mature DC-derived CXCL10 is pivotal to retain Th1 lymphocytes within T cell areas of draining LNs and optimize the Th1-mediated immune responses.
Yoneyama
Hiroyuki
H
Department of Molecular Preventive Medicine, School of Medicine and Core Research and Evolutional Science and Technology (CREST), The University of Tokyo, Tokyo 113-0033, Japan.
Narumi
Shosaku
S
Zhang
Yanyun
Y
Murai
Masako
M
Baggiolini
Marco
M
Lanzavecchia
Antonio
A
Ichida
Takafumi
T
Asakura
Hitoshi
H
Matsushima
Kouji
K
D000818:Animals; D054421:Chemokine CCL21; D054422:Chemokine CCL22; D054357:Chemokine CXCL10; D018925:Chemokines / Q000276:immunology / Q000494:pharmacology; D019742:Chemokines, CC / Q000378:metabolism; D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D006105:Granulomatous Disease, Chronic / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology*; D051379:Mice; D011425:Propionibacterium acnes / Q000276:immunology / Q000502:physiology; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
C515479:Ccl21c protein, mouse; C515483:Ccl22 protein, mouse; D054421:Chemokine CCL21; D054422:Chemokine CCL22; D054357:Chemokine CXCL10; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D015847:Interleukin-4; D007371:Interferon-gamma