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Stefan Martin

Publications and source records attributed to Stefan Martin.

5 recordsLinked to original sources
PubMed2006

CD8+ cytotoxic T cells induce relapsing colitis in normal mice.

BACKGROUND & AIMS: Most mouse models of IBD have emphasized an effector role of type-1 CD4+ T cells in colitis. The aim of this study was to develop a model of antigen-specific relapsing colitis to investigate the relative contribution of CD4+ and CD8+ effectors. METHODS: Balb/C mice were sensitized and challenged with a suboptimal dose of 2.4 dinitrobenzene sulfonic acid to generate a colonic delayed-type hypersensitivity response. The respective role of CD4+ and CD8+ T cells in the initiation of colitis was analyzed by in vivo monoclonal antibody depletion and cell-transfer experiments. Dynamic and function of the colitogenic effectors were studied by immunohistochemistry, fluorescence-activated cell sorter analysis, enzyme-linked immunospot assay, quantitative polymerase chain reaction, and in vivo CTL assays. RESULTS: Relapsing colitis rapidly occurred only after challenge of previously sensitized mice. Interferon-gamma-producing cytotoxic CD8+ T cells (Tc1) specific for hapten-modified self-proteins were generated in colon-draining lymph nodes on day 5 after sensitization, before the onset of disease. These CD8+ T cells were rapidly recruited upon challenge into colon lamina propria as granzyme B-expressing effectors exerting ex vivo cytotoxicity against syngeneic hapten-modified colonic epithelial cells. Colitis was prevented by in vivo antibody depletion of CD8+, but not of CD4+, T cells and could be induced in naive recipients within 48 hours after transfer of CD8+, but not CD4+, T cells purified from sensitized mice. CONCLUSIONS: Our data show that antigen-specific CD8+ T cells can induce relapsing colitis in normal mice and suggest that the cytolytic function of CD8 Tc1 against epithelial cells may initiate the intestinal inflammatory process.

Animals↗
PubMed2004

Dendritic cell immunization route determines CD8+ T cell trafficking to inflamed skin: role for tissue microenvironment and dendritic cells in establishment of T cell-homing subsets.

The effector/memory T cell pool branches in homing subsets selectively trafficking to organs such as gut or skin. Little is known about the critical factors in the generation of skin-homing CD8+ T cells, although they are crucial effectors in skin-restricted immune responses such as contact hypersensitivity and melanoma defense. In this study, we show that intracutaneous, but not i.v. injection of bone marrow-derived dendritic cells induced skin-homing CD8+ T cells with up-regulated E-selectin ligand expression and effector function in contact hypersensitivity. The skin-homing potential and E-selectin ligand expression remained stable in memory phase without further Ag contact. In contrast, i.p. injection induced T cells expressing the gut-homing integrin alpha(4)beta(7). Although differential expression of these adhesion molecules was strictly associated with the immunization route, the postulated skin-homing marker CCR4 was transiently up-regulated in all conditions. Interestingly, dendritic cells from different tissues effectively induced the corresponding homing markers on T cells in vitro. Our results suggest a crucial role for the tissue microenvironment and dendritic cells in the instruction of T cells for tissue-selective homing and demonstrate that Langerhans cells are specialized to target T cells to inflamed skin.

Adoptive Transfer↗
PubMed2003

A high frequency of allergen-specific CD8+ Tc1 cells is associated with the murine immune response to the contact sensitizer trinitrophenyl.

Chemical haptens induce a variety of allergic immune reactions by induction of hapten-specific T cells. Contact sensitizers such as the hapten trinitrochlorobenzene (TNCB) elicit an allergic response, which is confined to the area of antigen exposure. Despite this localized allergic response, we show here that the trinitrophenyl (TNP)-specific immune response is characterized by a rapid induction of CD8+ Tc1 type cytotoxic effector cells already after a single allergen contact which can be detected in all secondary lymphoid organs tested. We furthermore demonstrate that the rapid induction of CD8+ Tc1 effector cells correlates with an unusually high frequency of polyclonal TNP-specific CD8+ effector T cells with specificities for a variety of MHC class I binding TNP-peptides carrying the hapten in different positions. These data suggest that allergies to chemical haptens may in part be due to an unusually high frequency of polyclonal, allergen-specific effector cells which are detected in all secondary lymphoid organs.

Allergens↗
PubMed2003

Bacterial CpG-DNA aggravates immune complex glomerulonephritis: role of TLR9-mediated expression of chemokines and chemokine receptors.

Immune complex glomerulonephritis (GN) often deteriorates during infection with viruses and bacteria that, in contrast to mammals, have DNA that contains many unmethylated CpG motifs. Balb/c mice with horse apoferritin-induced GN (HAF-GN) were treated with either saline, CpG-oligodeoxynucleotides (ODN), or control GpC-ODN. Only CpG-ODN exacerbated HAF-GN with an increase of glomerular macrophages, which was associated with massive albuminuria and increased renal MCP-1/CCL2, RANTES/CCL5, CCR1, CCR2, and CCR5 mRNA expression. CpG-ODN induced a Th1 response as indicated by serum anti-HAF IgG(2a) titers, mesangial IgG(2a) deposits, and splenocyte IFN-gamma secretion. Messenger RNA for the CpG-DNA receptor Toll-like reeptor 9 (TLR9) was present in kidneys with HAF-GN but not in normal kidneys. The source of TLR9 mRNA in HAF-GN could be infiltrating macrophages or intrinsic renal cells, e.g., mesangial cells; but, in vitro, only murine J774 macrophages expressed TLR9. In J774 cells, CpG-ODN induced the chemokines MCP-1/CCL2 and RANTES/CCL5 and the chemokine receptors CCR1 and CCR5. It is concluded that CpG-DNA can aggravate preexisting GN via a shift toward a Th1 response but also by a novel pathway involving TLR9-mediated chemokine and chemokine receptor expression by macrophages, which may contribute to the enhanced glomerular macrophage recruitment and activation. This mechanism may be relevant during infection-triggered exacerbation of human immune-complex GN and other immune-mediated diseases in general.

Animals↗