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The role of decay accelerating factor in environmentally induced and idiopathic systemic autoimmune disease.

Toomey CB, Cauvi DM, Pollard KM - Autoimmune Dis (2014)

Bottom Line: Decay accelerating factor (DAF) plays a complex role in the immune system through complement-dependent and -independent regulation of innate and adaptive immunity.In contrast, DAF-mediated T cell activation leads to cytokine expression consistent with T regulatory cells.These observations are used to develop a hypothetical model to explain how DAF expression may impact T cell differentiation via interaction with CD97 leading to T regulatory cells, increased production of IL-10, and immune tolerance.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Duke University School of Medicine, Albert Eye Research Institute, Durham, NC 27710, USA.

ABSTRACT
Decay accelerating factor (DAF) plays a complex role in the immune system through complement-dependent and -independent regulation of innate and adaptive immunity. Over the past five years there has been accumulating evidence for a significant role of DAF in negatively regulating adaptive T-cell responses and autoimmunity in both humans and experimental models. This review discusses the relationship between DAF and the complement system and highlights major advances in our understanding of the biology of DAF in human disease, particularly systemic lupus erythematosus. The role of DAF in regulation of idiopathic and environmentally induced systemic autoimmunity is discussed including studies showing that reduction or absence of DAF is associated with autoimmunity. In contrast, DAF-mediated T cell activation leads to cytokine expression consistent with T regulatory cells. This is supported by studies showing that interaction between DAF and its molecular partner, CD97, modifies expression of autoimmunity promoting cytokines. These observations are used to develop a hypothetical model to explain how DAF expression may impact T cell differentiation via interaction with CD97 leading to T regulatory cells, increased production of IL-10, and immune tolerance.

No MeSH data available.


Related in: MedlinePlus

CD4+CD25− T cells in mHgIA-resistant DBA/2 possess the cytokine phenotype of regulatory T-cells. NZB and DBA/2 mice were exposed to PBS (white bar) or HgCl2 (black bar) for 5 weeks. Splenocytes were then cultured in the presence of PMA/ionomycin and CD4+CD25− T-cells analyzed for the cytokine phenotype of IL-10+IL-4− (Tr1 cells). (a) shows the percent of Tr1 cells in total spleen. (b) shows the percent of Tr1 cells in CD4+ cells. (c) shows the percent of Tr1 cells in CD4+CD25− cells. n = 4/group.
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fig4: CD4+CD25− T cells in mHgIA-resistant DBA/2 possess the cytokine phenotype of regulatory T-cells. NZB and DBA/2 mice were exposed to PBS (white bar) or HgCl2 (black bar) for 5 weeks. Splenocytes were then cultured in the presence of PMA/ionomycin and CD4+CD25− T-cells analyzed for the cytokine phenotype of IL-10+IL-4− (Tr1 cells). (a) shows the percent of Tr1 cells in total spleen. (b) shows the percent of Tr1 cells in CD4+ cells. (c) shows the percent of Tr1 cells in CD4+CD25− cells. n = 4/group.

Mentions: The increased expression of IL-10 in human and murine CD4+ T cells stimulated by anti-CD3 and rCD97 [19, 109] suggests a regulatory T-cell phenotype [110, 116, 117]. As CD55 is required for this response, we asked whether a difference in CD55 expression might affect the generation of regulatory T cells. NZB and DBA/2 mice have reduced and elevated CD55, respectively, and exposure to HgCl2 exacerbates autoimmunity in NZB while DBA/2 mice are resistant [103]. Thus regulatory T cells may be more common in DBA/2 than NZB mice. To examine this possibility NZB and DBA/2 mice were exposed to HgCl2 and splenocytes were then cultured in vitro in the presence of PMA/ionomycin and analyzed for the presence of markers of T regulatory type 1 (Tr1) (CD4+CD25−IL-10+IL-4−) cells [118]. This protocol increased CD4+ T cells in HgCl2 exposed DBA/2 mice but not in NZB mice (Figure 3(a)). This was an unexpected finding given that DBA/2 mice are resistant to mHgIA, however these cells were primarily of the CD4+CD25− type (Figure 3(b)) indicating that they were not conventionally activated CD4+ T cells which can express CD25 [103]. CD4+CD25− T cells were then examined for expression of both IL-10 and IL-4 to identify Tr1-like cells (Figure 4). In total spleen, Tr1-like cells were dramatically increased following HgCl2 in DBA/2 mice but were reduced in NZB mice (Figure 4(a)). A similar situation was found when only CD4+ cells in the spleen were analyzed (Figure 4(b)). Finally we asked what percentage of CD4+CD25− cells were IL-10+IL-4− and found that the vast majority in the DBA/2 mice possessed the cytokine phenotype of T regulatory cells while such cells were much fewer in number in the NZB mice (Figure 4(c)). The greater percentage of putative Tr1 cells in PBS treated DBA/2 mice compared to NZB mice and the changing percentages of Tr1-like cells following mercury exposure are consistent with the sensitivity of these strains to mercury-induced autoimmunity. We hypothesize that the constitutively reduced CD55 expression in NZB mice [103] reduces CD55-CD97 interaction and the generation of Tr1 cells but favors Th1 responses. In contrast, DBA/2 mice, with a higher level of CD55 that is not impacted by mercury exposure [103], are able to maintain a higher level of CD55-CD97 interaction which favors regulatory T-cell generation and tolerance to mHgIA.


The role of decay accelerating factor in environmentally induced and idiopathic systemic autoimmune disease.

Toomey CB, Cauvi DM, Pollard KM - Autoimmune Dis (2014)

CD4+CD25− T cells in mHgIA-resistant DBA/2 possess the cytokine phenotype of regulatory T-cells. NZB and DBA/2 mice were exposed to PBS (white bar) or HgCl2 (black bar) for 5 weeks. Splenocytes were then cultured in the presence of PMA/ionomycin and CD4+CD25− T-cells analyzed for the cytokine phenotype of IL-10+IL-4− (Tr1 cells). (a) shows the percent of Tr1 cells in total spleen. (b) shows the percent of Tr1 cells in CD4+ cells. (c) shows the percent of Tr1 cells in CD4+CD25− cells. n = 4/group.
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Related In: Results  -  Collection

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fig4: CD4+CD25− T cells in mHgIA-resistant DBA/2 possess the cytokine phenotype of regulatory T-cells. NZB and DBA/2 mice were exposed to PBS (white bar) or HgCl2 (black bar) for 5 weeks. Splenocytes were then cultured in the presence of PMA/ionomycin and CD4+CD25− T-cells analyzed for the cytokine phenotype of IL-10+IL-4− (Tr1 cells). (a) shows the percent of Tr1 cells in total spleen. (b) shows the percent of Tr1 cells in CD4+ cells. (c) shows the percent of Tr1 cells in CD4+CD25− cells. n = 4/group.
Mentions: The increased expression of IL-10 in human and murine CD4+ T cells stimulated by anti-CD3 and rCD97 [19, 109] suggests a regulatory T-cell phenotype [110, 116, 117]. As CD55 is required for this response, we asked whether a difference in CD55 expression might affect the generation of regulatory T cells. NZB and DBA/2 mice have reduced and elevated CD55, respectively, and exposure to HgCl2 exacerbates autoimmunity in NZB while DBA/2 mice are resistant [103]. Thus regulatory T cells may be more common in DBA/2 than NZB mice. To examine this possibility NZB and DBA/2 mice were exposed to HgCl2 and splenocytes were then cultured in vitro in the presence of PMA/ionomycin and analyzed for the presence of markers of T regulatory type 1 (Tr1) (CD4+CD25−IL-10+IL-4−) cells [118]. This protocol increased CD4+ T cells in HgCl2 exposed DBA/2 mice but not in NZB mice (Figure 3(a)). This was an unexpected finding given that DBA/2 mice are resistant to mHgIA, however these cells were primarily of the CD4+CD25− type (Figure 3(b)) indicating that they were not conventionally activated CD4+ T cells which can express CD25 [103]. CD4+CD25− T cells were then examined for expression of both IL-10 and IL-4 to identify Tr1-like cells (Figure 4). In total spleen, Tr1-like cells were dramatically increased following HgCl2 in DBA/2 mice but were reduced in NZB mice (Figure 4(a)). A similar situation was found when only CD4+ cells in the spleen were analyzed (Figure 4(b)). Finally we asked what percentage of CD4+CD25− cells were IL-10+IL-4− and found that the vast majority in the DBA/2 mice possessed the cytokine phenotype of T regulatory cells while such cells were much fewer in number in the NZB mice (Figure 4(c)). The greater percentage of putative Tr1 cells in PBS treated DBA/2 mice compared to NZB mice and the changing percentages of Tr1-like cells following mercury exposure are consistent with the sensitivity of these strains to mercury-induced autoimmunity. We hypothesize that the constitutively reduced CD55 expression in NZB mice [103] reduces CD55-CD97 interaction and the generation of Tr1 cells but favors Th1 responses. In contrast, DBA/2 mice, with a higher level of CD55 that is not impacted by mercury exposure [103], are able to maintain a higher level of CD55-CD97 interaction which favors regulatory T-cell generation and tolerance to mHgIA.

Bottom Line: Decay accelerating factor (DAF) plays a complex role in the immune system through complement-dependent and -independent regulation of innate and adaptive immunity.In contrast, DAF-mediated T cell activation leads to cytokine expression consistent with T regulatory cells.These observations are used to develop a hypothetical model to explain how DAF expression may impact T cell differentiation via interaction with CD97 leading to T regulatory cells, increased production of IL-10, and immune tolerance.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Duke University School of Medicine, Albert Eye Research Institute, Durham, NC 27710, USA.

ABSTRACT
Decay accelerating factor (DAF) plays a complex role in the immune system through complement-dependent and -independent regulation of innate and adaptive immunity. Over the past five years there has been accumulating evidence for a significant role of DAF in negatively regulating adaptive T-cell responses and autoimmunity in both humans and experimental models. This review discusses the relationship between DAF and the complement system and highlights major advances in our understanding of the biology of DAF in human disease, particularly systemic lupus erythematosus. The role of DAF in regulation of idiopathic and environmentally induced systemic autoimmunity is discussed including studies showing that reduction or absence of DAF is associated with autoimmunity. In contrast, DAF-mediated T cell activation leads to cytokine expression consistent with T regulatory cells. This is supported by studies showing that interaction between DAF and its molecular partner, CD97, modifies expression of autoimmunity promoting cytokines. These observations are used to develop a hypothetical model to explain how DAF expression may impact T cell differentiation via interaction with CD97 leading to T regulatory cells, increased production of IL-10, and immune tolerance.

No MeSH data available.


Related in: MedlinePlus