Autoimmune-Mediated Intestinal Inflammation–Impact and Regulation of Antigen-Specific CD8 + T Cells

Background & Aims: Few data exist regarding mechanisms of mucosal CD8 + T-cell reactivity to epithelial-specific antigen. To dissect the immunologic mechanisms underlying CD8 + T-cell dysregulation, reactivity to a self-antigen expressed in intestinal epithelium of mice bearing a major histocomp...

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Veröffentlicht in:Gastroenterology (New York, N.Y. 1943) N.Y. 1943), 2006-08, Vol.131 (2), p.510-524
Hauptverfasser: Westendorf, Astrid Maria, Fleissner, Diana, Deppenmeier, Stefanie, Gruber, Achim Dieter, Bruder, Dunja, Hansen, Wiebke, Liblau, Roland, Buer, Jan
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container_end_page 524
container_issue 2
container_start_page 510
container_title Gastroenterology (New York, N.Y. 1943)
container_volume 131
creator Westendorf, Astrid Maria
Fleissner, Diana
Deppenmeier, Stefanie
Gruber, Achim Dieter
Bruder, Dunja
Hansen, Wiebke
Liblau, Roland
Buer, Jan
description Background & Aims: Few data exist regarding mechanisms of mucosal CD8 + T-cell reactivity to epithelial-specific antigen. To dissect the immunologic mechanisms underlying CD8 + T-cell dysregulation, reactivity to a self-antigen expressed in intestinal epithelium of mice bearing a major histocompatibility complex class I–restricted T-cell receptor specific for this antigen was studied. In addition, antigen-specific regulatory CD4 + T cells induced in vivo were tested to control these autoreactive CD8 + T cells. Methods: Transgenic VILLIN-HA mice were mated with CL4-TCR transgenic mice. Alternatively, adoptive transfer of CL4-TCR transgenic CD8 + T cells into VILLIN-HA transgenic mice was performed to mimic spontaneous encounter of neoantigen. Mucosal CD8 + T cells were characterized under different conditions of tolerance, immunopathology, and active immunosuppression. Results: Transgenic CD8 + T cells from VILLIN-HA × CL4-TCR transgenic mice preferentially migrated and expanded in mucosal lymphoid tissues. Although transgenic CD8 + T cells showed signs of T-cell activation, they failed to cause tissue damage. This was accompanied by the induction/expansion of CD4 + and CD8 +, Foxp3-expressing T cells. In contrast, adoptive transfer of naive transgenic CD8 + T cells from CL4-TCR transgenic mice into VILLIN-HA transgenic mice induced severe intestinal inflammation with poor clinical course of disease. Transgenic CD8 + T cells secreted vigorous amounts of proinflammatory cytokines like interferon γ/tumor necrosis factor α. Strikingly, this acute wasting disease was significantly ameliorated by cotransfer of antigen-specific regulatory CD4 + T cells. Conclusions: Epithelial-specific antigen expression is sufficient to trigger severe antigen-specific CD8 + T-cell–mediated intestinal inflammation; this might be controlled by antigen-specific regulatory T cells under physiological conditions.
doi_str_mv 10.1053/j.gastro.2006.05.015
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To dissect the immunologic mechanisms underlying CD8 + T-cell dysregulation, reactivity to a self-antigen expressed in intestinal epithelium of mice bearing a major histocompatibility complex class I–restricted T-cell receptor specific for this antigen was studied. In addition, antigen-specific regulatory CD4 + T cells induced in vivo were tested to control these autoreactive CD8 + T cells. Methods: Transgenic VILLIN-HA mice were mated with CL4-TCR transgenic mice. Alternatively, adoptive transfer of CL4-TCR transgenic CD8 + T cells into VILLIN-HA transgenic mice was performed to mimic spontaneous encounter of neoantigen. Mucosal CD8 + T cells were characterized under different conditions of tolerance, immunopathology, and active immunosuppression. Results: Transgenic CD8 + T cells from VILLIN-HA × CL4-TCR transgenic mice preferentially migrated and expanded in mucosal lymphoid tissues. Although transgenic CD8 + T cells showed signs of T-cell activation, they failed to cause tissue damage. This was accompanied by the induction/expansion of CD4 + and CD8 +, Foxp3-expressing T cells. In contrast, adoptive transfer of naive transgenic CD8 + T cells from CL4-TCR transgenic mice into VILLIN-HA transgenic mice induced severe intestinal inflammation with poor clinical course of disease. Transgenic CD8 + T cells secreted vigorous amounts of proinflammatory cytokines like interferon γ/tumor necrosis factor α. Strikingly, this acute wasting disease was significantly ameliorated by cotransfer of antigen-specific regulatory CD4 + T cells. 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Although transgenic CD8 + T cells showed signs of T-cell activation, they failed to cause tissue damage. This was accompanied by the induction/expansion of CD4 + and CD8 +, Foxp3-expressing T cells. In contrast, adoptive transfer of naive transgenic CD8 + T cells from CL4-TCR transgenic mice into VILLIN-HA transgenic mice induced severe intestinal inflammation with poor clinical course of disease. Transgenic CD8 + T cells secreted vigorous amounts of proinflammatory cytokines like interferon γ/tumor necrosis factor α. Strikingly, this acute wasting disease was significantly ameliorated by cotransfer of antigen-specific regulatory CD4 + T cells. 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Aims: Few data exist regarding mechanisms of mucosal CD8 + T-cell reactivity to epithelial-specific antigen. To dissect the immunologic mechanisms underlying CD8 + T-cell dysregulation, reactivity to a self-antigen expressed in intestinal epithelium of mice bearing a major histocompatibility complex class I–restricted T-cell receptor specific for this antigen was studied. In addition, antigen-specific regulatory CD4 + T cells induced in vivo were tested to control these autoreactive CD8 + T cells. Methods: Transgenic VILLIN-HA mice were mated with CL4-TCR transgenic mice. Alternatively, adoptive transfer of CL4-TCR transgenic CD8 + T cells into VILLIN-HA transgenic mice was performed to mimic spontaneous encounter of neoantigen. Mucosal CD8 + T cells were characterized under different conditions of tolerance, immunopathology, and active immunosuppression. Results: Transgenic CD8 + T cells from VILLIN-HA × CL4-TCR transgenic mice preferentially migrated and expanded in mucosal lymphoid tissues. Although transgenic CD8 + T cells showed signs of T-cell activation, they failed to cause tissue damage. This was accompanied by the induction/expansion of CD4 + and CD8 +, Foxp3-expressing T cells. In contrast, adoptive transfer of naive transgenic CD8 + T cells from CL4-TCR transgenic mice into VILLIN-HA transgenic mice induced severe intestinal inflammation with poor clinical course of disease. Transgenic CD8 + T cells secreted vigorous amounts of proinflammatory cytokines like interferon γ/tumor necrosis factor α. Strikingly, this acute wasting disease was significantly ameliorated by cotransfer of antigen-specific regulatory CD4 + T cells. Conclusions: Epithelial-specific antigen expression is sufficient to trigger severe antigen-specific CD8 + T-cell–mediated intestinal inflammation; this might be controlled by antigen-specific regulatory T cells under physiological conditions.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>16890605</pmid><doi>10.1053/j.gastro.2006.05.015</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record>
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subjects Animals
Autoimmunity
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - pathology
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - pathology
Cell Movement
Disease Progression
Enteritis - immunology
Enteritis - pathology
Flow Cytometry
Intestinal Mucosa - immunology
Intestinal Mucosa - pathology
Lymphocyte Activation - immunology
Mice
Mice, Transgenic
Phenotype
title Autoimmune-Mediated Intestinal Inflammation–Impact and Regulation of Antigen-Specific CD8 + T Cells
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