Limits...
T helper 1 and T helper 2 cells are pathogenic in an antigen-specific model of colitis.

Iqbal N, Oliver JR, Wagner FH, Lazenby AS, Elson CO, Weaver CT - J. Exp. Med. (2002)

Bottom Line: Transfer of antigen-naive DO11.RAG-2(-/-) T cells into recipients colonized with OVA-E. coli resulted in enhanced intestinal recruitment and cell cycling of OVA-specific T cells; however, there was no development of disease.The histopathologic features of disease induced by Th1 and Th2 transfers were distinct, but disease severity was comparable.Induction of disease by both Th1 and Th2 transfers was dependent on bacterially associated OVA.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.

ABSTRACT
Dysregulated T cell responses to enteric bacteria have been implicated as a common mechanism underlying pathogenesis in rodent models of colitis. However, the bacterial species and T cell specificities that induce disease have been poorly defined. We have developed a model system in which target antigen, bacterial host, and corresponding T cell specificity are defined. OVA-specific T cells from DO11.RAG-2(-/-) TCR transgenic mice were transferred into RAG-2(-/-) recipients whose intestinal tracts were colonized with OVA-expressing or control Escherichia coli. Transfer of antigen-naive DO11.RAG-2(-/-) T cells into recipients colonized with OVA-E. coli resulted in enhanced intestinal recruitment and cell cycling of OVA-specific T cells; however, there was no development of disease. In contrast, transfer of polarized T helper (Th) 1 and Th2 populations resulted in severe wasting and colitis in recipients colonized with OVA-expressing but not control E. coli. The histopathologic features of disease induced by Th1 and Th2 transfers were distinct, but disease severity was comparable. Induction of disease by both Th1 and Th2 transfers was dependent on bacterially associated OVA. These results establish that a single bacterially associated antigen can drive the progression of colitis mediated by both Th1 and Th2 cells and provide a new model for understanding the immunoregulatory interactions between T cells responsive to gut floral antigens.

Show MeSH

Related in: MedlinePlus

T cells recovered from colitic mice retain a polarized Th1 or Th2 phenotype. Intestinal tissues from Th1 and Th2 adoptive transfer recipients colonized with pnir15.OVA-E. coli were recovered and processed for isolation of LP lymphocytes 8 wk after transfer (Materials and Methods). CD4+ T cells were purified by magnetic sorting and stimulated with plate-bound anti-CD3 and anti-CD28 for 72 h. Culture supernatants were assayed for IFN-γ, IL-4, and IL-10 by ELISA. Data are the means and SD of triplicate determinations for T cells pooled from 6–10 mice per group. The detection limits of the respective ELISA assays are indicated for those values that were not greater than background (P < 0.01).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2196021&req=5

fig7: T cells recovered from colitic mice retain a polarized Th1 or Th2 phenotype. Intestinal tissues from Th1 and Th2 adoptive transfer recipients colonized with pnir15.OVA-E. coli were recovered and processed for isolation of LP lymphocytes 8 wk after transfer (Materials and Methods). CD4+ T cells were purified by magnetic sorting and stimulated with plate-bound anti-CD3 and anti-CD28 for 72 h. Culture supernatants were assayed for IFN-γ, IL-4, and IL-10 by ELISA. Data are the means and SD of triplicate determinations for T cells pooled from 6–10 mice per group. The detection limits of the respective ELISA assays are indicated for those values that were not greater than background (P < 0.01).

Mentions: The distinct patterns of inflammation in diseased colons of Th1- and Th2-reconstituted mice strongly suggested that either effector T cell population could induce a pathogenic response. However, given the short-term in vitro polarizations before transfer, and evidence for some heterogeneity of cytokine profiles of the starting T cell populations (see RPA analysis, Fig. 3), it was possible that a shift in cytokine phenotype might have occurred in vivo. To determine if the T cells present in colitic lesions retained a similar cytokine phenotype to those of the original T cell populations transferred, cytokine analyses were performed on recovered T cells (Fig. 7) . CD4+ T cells isolated from the intestinal LP of pnir15.OVA-E. coli-colonized recipients reconstituted with Th1- or Th2-polarized DO11. RAG-2−/− T cells were restimulated in vitro with plate-bound anti-CD3 plus anti-CD28 and assayed for production of IFN-γ, IL-4, and IL-10. Stimulated T cells from the LP of Th1-reconstituted mice produced abundant IFN-γ and no detectable IL-4 or IL-10; LP T cells recovered from Th2-reconstituted mice produced IL-4 and IL-10, but no detectable IFN-γ. Thus, the distinct histopathologies were associated with strongly polarized Th1 or Th2 cells in the diseased intestinal tissues.


T helper 1 and T helper 2 cells are pathogenic in an antigen-specific model of colitis.

Iqbal N, Oliver JR, Wagner FH, Lazenby AS, Elson CO, Weaver CT - J. Exp. Med. (2002)

T cells recovered from colitic mice retain a polarized Th1 or Th2 phenotype. Intestinal tissues from Th1 and Th2 adoptive transfer recipients colonized with pnir15.OVA-E. coli were recovered and processed for isolation of LP lymphocytes 8 wk after transfer (Materials and Methods). CD4+ T cells were purified by magnetic sorting and stimulated with plate-bound anti-CD3 and anti-CD28 for 72 h. Culture supernatants were assayed for IFN-γ, IL-4, and IL-10 by ELISA. Data are the means and SD of triplicate determinations for T cells pooled from 6–10 mice per group. The detection limits of the respective ELISA assays are indicated for those values that were not greater than background (P < 0.01).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196021&req=5

fig7: T cells recovered from colitic mice retain a polarized Th1 or Th2 phenotype. Intestinal tissues from Th1 and Th2 adoptive transfer recipients colonized with pnir15.OVA-E. coli were recovered and processed for isolation of LP lymphocytes 8 wk after transfer (Materials and Methods). CD4+ T cells were purified by magnetic sorting and stimulated with plate-bound anti-CD3 and anti-CD28 for 72 h. Culture supernatants were assayed for IFN-γ, IL-4, and IL-10 by ELISA. Data are the means and SD of triplicate determinations for T cells pooled from 6–10 mice per group. The detection limits of the respective ELISA assays are indicated for those values that were not greater than background (P < 0.01).
Mentions: The distinct patterns of inflammation in diseased colons of Th1- and Th2-reconstituted mice strongly suggested that either effector T cell population could induce a pathogenic response. However, given the short-term in vitro polarizations before transfer, and evidence for some heterogeneity of cytokine profiles of the starting T cell populations (see RPA analysis, Fig. 3), it was possible that a shift in cytokine phenotype might have occurred in vivo. To determine if the T cells present in colitic lesions retained a similar cytokine phenotype to those of the original T cell populations transferred, cytokine analyses were performed on recovered T cells (Fig. 7) . CD4+ T cells isolated from the intestinal LP of pnir15.OVA-E. coli-colonized recipients reconstituted with Th1- or Th2-polarized DO11. RAG-2−/− T cells were restimulated in vitro with plate-bound anti-CD3 plus anti-CD28 and assayed for production of IFN-γ, IL-4, and IL-10. Stimulated T cells from the LP of Th1-reconstituted mice produced abundant IFN-γ and no detectable IL-4 or IL-10; LP T cells recovered from Th2-reconstituted mice produced IL-4 and IL-10, but no detectable IFN-γ. Thus, the distinct histopathologies were associated with strongly polarized Th1 or Th2 cells in the diseased intestinal tissues.

Bottom Line: Transfer of antigen-naive DO11.RAG-2(-/-) T cells into recipients colonized with OVA-E. coli resulted in enhanced intestinal recruitment and cell cycling of OVA-specific T cells; however, there was no development of disease.The histopathologic features of disease induced by Th1 and Th2 transfers were distinct, but disease severity was comparable.Induction of disease by both Th1 and Th2 transfers was dependent on bacterially associated OVA.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.

ABSTRACT
Dysregulated T cell responses to enteric bacteria have been implicated as a common mechanism underlying pathogenesis in rodent models of colitis. However, the bacterial species and T cell specificities that induce disease have been poorly defined. We have developed a model system in which target antigen, bacterial host, and corresponding T cell specificity are defined. OVA-specific T cells from DO11.RAG-2(-/-) TCR transgenic mice were transferred into RAG-2(-/-) recipients whose intestinal tracts were colonized with OVA-expressing or control Escherichia coli. Transfer of antigen-naive DO11.RAG-2(-/-) T cells into recipients colonized with OVA-E. coli resulted in enhanced intestinal recruitment and cell cycling of OVA-specific T cells; however, there was no development of disease. In contrast, transfer of polarized T helper (Th) 1 and Th2 populations resulted in severe wasting and colitis in recipients colonized with OVA-expressing but not control E. coli. The histopathologic features of disease induced by Th1 and Th2 transfers were distinct, but disease severity was comparable. Induction of disease by both Th1 and Th2 transfers was dependent on bacterially associated OVA. These results establish that a single bacterially associated antigen can drive the progression of colitis mediated by both Th1 and Th2 cells and provide a new model for understanding the immunoregulatory interactions between T cells responsive to gut floral antigens.

Show MeSH
Related in: MedlinePlus