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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.

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DO11.RAG-2−/−/RAG-2−/− recipients fed OVA do not develop colitis. RAG-2−/− recipients were reconstituted with 106 CD4+ Th1 or Th2 cells generated from DO11.RAG-2−/− donors. 1 d before T cell reconstitution, recipients were colonized with 1010 CFU of the indicated bacteria, and maintained with biweekly administration of an additional dose of 1010 CFU bacteria. 8 wk after reconstitution, mice were killed and necropsied. Colonic and cecal disease was scored as described in Materials and Methods; mean total scores and SEM are indicated (bottom). BrdU (0.8 mg/ml) was added to the drinking water of indicated groups for 9 d before sacrifice; intestinal tissues were processed and evaluated as in Table II for CD3+ cell densities (middle) and BrdU incorporation (top). Data are from two experiments and are the means ± SEM from 4–8 animals per group. Values that differed significantly from control (P < 0.05) are indicated with an asterisk. ND, not done.
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fig8: DO11.RAG-2−/−/RAG-2−/− recipients fed OVA do not develop colitis. RAG-2−/− recipients were reconstituted with 106 CD4+ Th1 or Th2 cells generated from DO11.RAG-2−/− donors. 1 d before T cell reconstitution, recipients were colonized with 1010 CFU of the indicated bacteria, and maintained with biweekly administration of an additional dose of 1010 CFU bacteria. 8 wk after reconstitution, mice were killed and necropsied. Colonic and cecal disease was scored as described in Materials and Methods; mean total scores and SEM are indicated (bottom). BrdU (0.8 mg/ml) was added to the drinking water of indicated groups for 9 d before sacrifice; intestinal tissues were processed and evaluated as in Table II for CD3+ cell densities (middle) and BrdU incorporation (top). Data are from two experiments and are the means ± SEM from 4–8 animals per group. Values that differed significantly from control (P < 0.05) are indicated with an asterisk. ND, not done.

Mentions: Previous studies have shown that continuous oral delivery of free OVA at a dose of 0.1 μg/ml could activate DO11.10-derived Tr1 regulatory cells to control colitis development in adoptively transferred mice (47). We sought to determine if free OVA delivered to RAG-2−/− mice reconstituted with DO11.RAG-2−/− Th1 and Th2 cells would be sufficient to cause intestinal disease, or whether bacterially associated OVA was required. RAG-2−/− mice were reconstituted with DO11.RAG-2−/− Th1 and Th2 cells and were challenged with free versus bacterially associated OVA. Free OVA was delivered continuously in the drinking water over an 8-wk course, with or without pnir15.TET-E. coli colonization to control for potential nonspecific adjuvanticity of the E. coli organisms used for colonization (Fig. 8) . Control animals received no OVA or pnir15.OVA-E. coli.


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)

DO11.RAG-2−/−/RAG-2−/− recipients fed OVA do not develop colitis. RAG-2−/− recipients were reconstituted with 106 CD4+ Th1 or Th2 cells generated from DO11.RAG-2−/− donors. 1 d before T cell reconstitution, recipients were colonized with 1010 CFU of the indicated bacteria, and maintained with biweekly administration of an additional dose of 1010 CFU bacteria. 8 wk after reconstitution, mice were killed and necropsied. Colonic and cecal disease was scored as described in Materials and Methods; mean total scores and SEM are indicated (bottom). BrdU (0.8 mg/ml) was added to the drinking water of indicated groups for 9 d before sacrifice; intestinal tissues were processed and evaluated as in Table II for CD3+ cell densities (middle) and BrdU incorporation (top). Data are from two experiments and are the means ± SEM from 4–8 animals per group. Values that differed significantly from control (P < 0.05) are indicated with an asterisk. ND, not done.
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Related In: Results  -  Collection

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

fig8: DO11.RAG-2−/−/RAG-2−/− recipients fed OVA do not develop colitis. RAG-2−/− recipients were reconstituted with 106 CD4+ Th1 or Th2 cells generated from DO11.RAG-2−/− donors. 1 d before T cell reconstitution, recipients were colonized with 1010 CFU of the indicated bacteria, and maintained with biweekly administration of an additional dose of 1010 CFU bacteria. 8 wk after reconstitution, mice were killed and necropsied. Colonic and cecal disease was scored as described in Materials and Methods; mean total scores and SEM are indicated (bottom). BrdU (0.8 mg/ml) was added to the drinking water of indicated groups for 9 d before sacrifice; intestinal tissues were processed and evaluated as in Table II for CD3+ cell densities (middle) and BrdU incorporation (top). Data are from two experiments and are the means ± SEM from 4–8 animals per group. Values that differed significantly from control (P < 0.05) are indicated with an asterisk. ND, not done.
Mentions: Previous studies have shown that continuous oral delivery of free OVA at a dose of 0.1 μg/ml could activate DO11.10-derived Tr1 regulatory cells to control colitis development in adoptively transferred mice (47). We sought to determine if free OVA delivered to RAG-2−/− mice reconstituted with DO11.RAG-2−/− Th1 and Th2 cells would be sufficient to cause intestinal disease, or whether bacterially associated OVA was required. RAG-2−/− mice were reconstituted with DO11.RAG-2−/− Th1 and Th2 cells and were challenged with free versus bacterially associated OVA. Free OVA was delivered continuously in the drinking water over an 8-wk course, with or without pnir15.TET-E. coli colonization to control for potential nonspecific adjuvanticity of the E. coli organisms used for colonization (Fig. 8) . Control animals received no OVA or pnir15.OVA-E. coli.

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