Regulatory T cells (T reg cells) that express the transcription factor Foxp3 suppress the activity of other cells. Here we show that interleukin 10 (IL-10) produced by CD11b + myeloid cells in recombination-activating gene 1-deficient (Rag1 −/− ) recipient mice was needed to prevent the colitis induced by transferred CD4 + CD45RB hi T cells. In Il10 −/− Rag1 −/− mice, T reg cells failed to maintain Foxp3 expression and regulatory activity. The loss of Foxp3 expression occurred only in recipients with colitis, which indicates that the requirement for IL-10 is manifested in the presence of inflammation. IL-10 receptor-deficient (Il10rb −/− ) T reg cells also failed to maintain Foxp3 expression, which suggested that host IL-10 acted directly on the T reg cells. Our data indicate that IL-10 released from myeloid cells acts in a paracrine manner on T reg cells to maintain Foxp3 expression. CD4 + regulatory T cells (T reg cells) express the transcription factor Foxp3 (A002750), which is required for their suppressive function. A T cell-transfer model of colitis has been widely used to study the function of T reg cells in vivo. When CD4 + CD45RB hi T cells are transferred into immunodeficient mice, some of the transferred T cells secrete proinflammatory cytokines and induce an inflammatory bowel disease-like syndrome 1,2 . Cotransfer of sufficient numbers of T reg cells can prevent or even cure this disease 3,4 . The transferred T reg cell populations expand considerably in vivo, and most maintain Foxp3 expression 5,6 .Mice deficient in interleukin 10 (IL-10 (A001243); Il10 −/− mice) or the IL-10 receptor β-chain (IL-10Rβ (A001245); Il10rb −/− mice) develop spontaneous inflammation of the large intestine, a process dominated by a T helper type 1 immune response7 ,8 . Many cell types can produce IL-10, however, and therefore the IL-10 source(s) needed to prevent inflammation must be identified. Much emphasis has been placed on the role of IL-10 released by CD4 + T cells, and in fact mice with conditional deletion of IL-10 in the CD4 + subset develop spontaneous inflammation of the intestine 9 . Mice with deletion of IL-10 solely in Foxp3 + cells also develop inflammation in the intestine and elsewhere, although the pathogenesis is less intense than that in mice completely lacking . Transgenic mice that overexpress IL-10 in intestinal epithelial cells are protected from colitis11, which suggests that IL-10 from nonlymphoid sources can be beneficial, although altered expression in the transgenic mice may not be physiologically relevant. NIH Public AccessTo further elucidate the cellular and molecular basis of the function of IL-10 in regulating colitis, we used the T cell-transfer model described above. We found that IL-10 from nonlymphoid cells, particularly CD11b + CD11c + cells, had an unexpectedly important influence on the development of colitis. Furthermore, we provide evidence that this IL-10 acted in part on T reg cells to maintain their expression of Foxp3, which was otherwise lost in inflammatory condit...

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We have studied the recruitment and roles of distinct dendritic cell (DC) precursors from the circulation into Propionibacterium acnes–induced granulomas in mouse liver. During infection, F4/80−B220−CD11c+ DC precursors appeared in the circulation, migrated into the perisinusoidal space, and matured within newly formed granulomas. Recruited DCs later migrated to the portal area to interact with T cells in what we term “portal tract–associated lymphoid tissue” (PALT). Macrophage inflammatory protein 1α attracted blood DC precursors to the sinusoidal granuloma, whereas secondary lymphoid organ chemokine (SLC) attracted mature DCs to the newly identified PALT. Anti-SLC antibody diminished PALT expansion while exacerbating granuloma formation. Therefore, circulating DC precursors can migrate into a solid organ like liver, and participate in the granulomatous reaction in response to specific chemokines.

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-γ–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-γ 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.

Acute graft-versus-host disease (a-GVHD) is initiated primarily by immunologically competent cytotoxic T cells (CTLs) that express anti-host specificities. However, the host lymphoid compartment in which these precursor CTLs are initially stimulated remains unclear. Here we show that gut Peyer's patches (PPs) are required to activate anti-host CTL responses in a well characterized murine acute graft-versus-host reaction (a-GVHR) model, involving transfer of parent lymphocytes into F1 hybrid recipients. The a-GVHR was prevented when recruitment of donor T cells into PP was interrupted either by disrupting the gene encoding chemokine receptor CCR5 or by blocking integrin alpha(4)beta(7)-MAdCAM-1 (mucosal vascular addressin) interactions. Mice deficient for PPs failed to develop a-GVHD in two models of disease induction. Thus, blockade of CTL generation in PPs might offer new strategies for circumventing a-GVHD.

Thymus and activation-regulated chemokine (TARC) is a recently identified lymphocyte-directed CC chemokine which specifically chemoattracts T helper type 2 CD4 ϩ T cells in human. To establish the pathophysiological roles of TARC in vivo, we investigated whether a monoclonal antibody (mAb) against TARC could inhibit the induction of hepatic lesions in murine model using Propionibacterium acnes and lipopolysaccharide (LPS). P . acnes -induced intrahepatic granuloma formation in the priming phase is essential to the subsequent liver injury elicited by a low dose of LPS.The priming phase appears to be dominated by Th1 type immune responses determined by the profile of chemokine and chemokine receptor expression. TARC was selectively produced by granuloma-forming cells, and CC chemokine receptor 4 (CCR4)-expressing CD4 ϩ T cells migrated into the liver after LPS administration. In vivo injection of anti-TARC mAb just before LPS administration protected the mice from acute lethal liver damage, which was accompanied by a significant reduction of both CCR4 mRNA expression and IL-4 production by liver-infiltrating CD4 ϩ T cells. Moreover, both TNF-␣ and Fas ligand expressions in the liver were decreased by anti-TARC treatment. These results suggest that recruitment of IL-4-producing CCR4 ϩ CD4ϩ T cells by granuloma-derived TARC into the liver parenchyma may be a key cause of massive liver injury after systemic LPS administration. ( J. Clin. Invest. 1998Invest. . 102: 1933Invest. -1941

Ligation of the chemokine receptor CCR2 on monocytes and macrophages with its ligand CCL2 results in activation of the cascade consisting of phosphatidylinositol-3-OH kinase (PI(3)K), the small G protein Rac and lamellipodium protrusion. We show here that a unique clathrin heavy-chain repeat homology protein, FROUNT, directly bound activated CCR2 and formed clusters at the cell front during chemotaxis. Overexpression of FROUNT amplified the chemokine-elicited PI(3)K-Rac-lamellipodium protrusion cascade and subsequent chemotaxis. Blocking FROUNT function by using a truncated mutant or antisense strategy substantially diminished signaling via CCR2. In a mouse peritonitis model, suppression of endogenous FROUNT markedly prevented macrophage infiltration. Thus, FROUNT links activated CCR2 to the PI(3)K-Rac-lamellipodium protrusion cascade and could be a therapeutic target in chronic inflammatory immune diseases associated with macrophage infiltration.