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Murine lupus susceptibility locus Sle1a requires the expression of two sub-loci to induce inflammatory T cells.

Cuda CM, Zeumer L, Sobel ES, Croker BP, Morel L - Genes Immun. (2010)

Bottom Line: Sle1a.1, and to a lesser extent Sle1a.2, significantly affected CD4(+) T-cell activation as well as Treg differentiation and function.As the Sle1a.1 and Sle1a.2 intervals contain only 1 and 15 known genes, respectively, this study considerably reduces the number of candidate genes responsible for the production of autoreactive T cells.These results also show that the Sle1 locus is an excellent model for the genetic architecture of lupus, in which a major obligate phenotype results from the coexpression of multiple genetic variants with individual weak effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, 32610-0275, USA.

ABSTRACT
The NZM2410-derived Sle1a lupus susceptibility locus induces activated autoreactive CD4(+) T cells and reduces the number and function of Foxp3(+) regulatory T cells (Tregs). In this study, we first showed that Sle1a contributes to autoimmunity by increasing antinuclear antibody production when expressed on either NZB or NZW heterozygous genomes, and by enhancing the chronic graft versus host disease response indicating an expansion of the autoreactive B-cell pool. Screening two non-overlapping recombinants, the Sle1a.1 and Sle1a.2 intervals that cover the entire Sle1a locus, revealed that both Sle1a.1 and Sle1a.2 were necessary for the full Sle1a phenotype. Sle1a.1, and to a lesser extent Sle1a.2, significantly affected CD4(+) T-cell activation as well as Treg differentiation and function. Sle1a.2 also increased the production of autoreactive B cells. As the Sle1a.1 and Sle1a.2 intervals contain only 1 and 15 known genes, respectively, this study considerably reduces the number of candidate genes responsible for the production of autoreactive T cells. These results also show that the Sle1 locus is an excellent model for the genetic architecture of lupus, in which a major obligate phenotype results from the coexpression of multiple genetic variants with individual weak effects.

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Both Sle1a.1 and Sle1a.2 decreased in vitro Treg suppression. A–B. Representative FACS plots and quantitation of CD4+ Foxp3+ splenocytes. C–D. Representative histograms of CD62L staining in CD4+ CD25+ gated splenocytes and corresponding quantitation. The light gray filled histogram shows the isotype control, the dark gray filled histogram shows B6, while thick, thin and dashed black lines represent B6.Sle1a, B6.Sle1a.1 and B6.Sle1a.2, respectively. E. B6 (black), Sle1a.1 (white) and Sle1a.2 (grey) Treg suppression of B6 Teff proliferation at the indicated ratios in the presence of B6 APCs. For each strain, proliferation in the presence of Treg at various ratios was compared to proliferation in the absence of Tregs. Sle1a.1 (F) or Sle1a.2 (G) expression in Tregs, Teffs, or APCs affects the extent of the inhibition of Teff proliferation. The inhibition of Teff proliferation in presence of 1:1, 1:4, or 1:16 Treg:Teff ratios is expressed as a percentage of the proliferation induced in the absence of Tregs for each condition. Data were collected from 5–7 month old mice. E–G graphs are representative of 2 independent assays each with 3–4 mice per strain. All comparisons were performed with B6 values. *: p<0.05, **: p<0.01, ***: p<0.001.
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Figure 5: Both Sle1a.1 and Sle1a.2 decreased in vitro Treg suppression. A–B. Representative FACS plots and quantitation of CD4+ Foxp3+ splenocytes. C–D. Representative histograms of CD62L staining in CD4+ CD25+ gated splenocytes and corresponding quantitation. The light gray filled histogram shows the isotype control, the dark gray filled histogram shows B6, while thick, thin and dashed black lines represent B6.Sle1a, B6.Sle1a.1 and B6.Sle1a.2, respectively. E. B6 (black), Sle1a.1 (white) and Sle1a.2 (grey) Treg suppression of B6 Teff proliferation at the indicated ratios in the presence of B6 APCs. For each strain, proliferation in the presence of Treg at various ratios was compared to proliferation in the absence of Tregs. Sle1a.1 (F) or Sle1a.2 (G) expression in Tregs, Teffs, or APCs affects the extent of the inhibition of Teff proliferation. The inhibition of Teff proliferation in presence of 1:1, 1:4, or 1:16 Treg:Teff ratios is expressed as a percentage of the proliferation induced in the absence of Tregs for each condition. Data were collected from 5–7 month old mice. E–G graphs are representative of 2 independent assays each with 3–4 mice per strain. All comparisons were performed with B6 values. *: p<0.05, **: p<0.01, ***: p<0.001.

Mentions: Sle1a reduces the number of splenic Tregs,18,20 and we found a comparable decrease induced by either Sle1a.1 or Sle1a.2 (Fig. 5A and B). Tregs are CD4+ CD25+ CD62L+, a T cell subset that is significantly decreased in B6.Sle1a mice, indicating that Sle1a is associated with a higher proportion of recently activated CD4+ CD25+ T cells.20 This phenotype also mapped to both Sle1a.1 and Sle1a.2 (Fig. 5C). Overall these results indicate that both Sle1a.1 and Sle1a.2 contribute to a reduced Treg compartment.


Murine lupus susceptibility locus Sle1a requires the expression of two sub-loci to induce inflammatory T cells.

Cuda CM, Zeumer L, Sobel ES, Croker BP, Morel L - Genes Immun. (2010)

Both Sle1a.1 and Sle1a.2 decreased in vitro Treg suppression. A–B. Representative FACS plots and quantitation of CD4+ Foxp3+ splenocytes. C–D. Representative histograms of CD62L staining in CD4+ CD25+ gated splenocytes and corresponding quantitation. The light gray filled histogram shows the isotype control, the dark gray filled histogram shows B6, while thick, thin and dashed black lines represent B6.Sle1a, B6.Sle1a.1 and B6.Sle1a.2, respectively. E. B6 (black), Sle1a.1 (white) and Sle1a.2 (grey) Treg suppression of B6 Teff proliferation at the indicated ratios in the presence of B6 APCs. For each strain, proliferation in the presence of Treg at various ratios was compared to proliferation in the absence of Tregs. Sle1a.1 (F) or Sle1a.2 (G) expression in Tregs, Teffs, or APCs affects the extent of the inhibition of Teff proliferation. The inhibition of Teff proliferation in presence of 1:1, 1:4, or 1:16 Treg:Teff ratios is expressed as a percentage of the proliferation induced in the absence of Tregs for each condition. Data were collected from 5–7 month old mice. E–G graphs are representative of 2 independent assays each with 3–4 mice per strain. All comparisons were performed with B6 values. *: p<0.05, **: p<0.01, ***: p<0.001.
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Figure 5: Both Sle1a.1 and Sle1a.2 decreased in vitro Treg suppression. A–B. Representative FACS plots and quantitation of CD4+ Foxp3+ splenocytes. C–D. Representative histograms of CD62L staining in CD4+ CD25+ gated splenocytes and corresponding quantitation. The light gray filled histogram shows the isotype control, the dark gray filled histogram shows B6, while thick, thin and dashed black lines represent B6.Sle1a, B6.Sle1a.1 and B6.Sle1a.2, respectively. E. B6 (black), Sle1a.1 (white) and Sle1a.2 (grey) Treg suppression of B6 Teff proliferation at the indicated ratios in the presence of B6 APCs. For each strain, proliferation in the presence of Treg at various ratios was compared to proliferation in the absence of Tregs. Sle1a.1 (F) or Sle1a.2 (G) expression in Tregs, Teffs, or APCs affects the extent of the inhibition of Teff proliferation. The inhibition of Teff proliferation in presence of 1:1, 1:4, or 1:16 Treg:Teff ratios is expressed as a percentage of the proliferation induced in the absence of Tregs for each condition. Data were collected from 5–7 month old mice. E–G graphs are representative of 2 independent assays each with 3–4 mice per strain. All comparisons were performed with B6 values. *: p<0.05, **: p<0.01, ***: p<0.001.
Mentions: Sle1a reduces the number of splenic Tregs,18,20 and we found a comparable decrease induced by either Sle1a.1 or Sle1a.2 (Fig. 5A and B). Tregs are CD4+ CD25+ CD62L+, a T cell subset that is significantly decreased in B6.Sle1a mice, indicating that Sle1a is associated with a higher proportion of recently activated CD4+ CD25+ T cells.20 This phenotype also mapped to both Sle1a.1 and Sle1a.2 (Fig. 5C). Overall these results indicate that both Sle1a.1 and Sle1a.2 contribute to a reduced Treg compartment.

Bottom Line: Sle1a.1, and to a lesser extent Sle1a.2, significantly affected CD4(+) T-cell activation as well as Treg differentiation and function.As the Sle1a.1 and Sle1a.2 intervals contain only 1 and 15 known genes, respectively, this study considerably reduces the number of candidate genes responsible for the production of autoreactive T cells.These results also show that the Sle1 locus is an excellent model for the genetic architecture of lupus, in which a major obligate phenotype results from the coexpression of multiple genetic variants with individual weak effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, 32610-0275, USA.

ABSTRACT
The NZM2410-derived Sle1a lupus susceptibility locus induces activated autoreactive CD4(+) T cells and reduces the number and function of Foxp3(+) regulatory T cells (Tregs). In this study, we first showed that Sle1a contributes to autoimmunity by increasing antinuclear antibody production when expressed on either NZB or NZW heterozygous genomes, and by enhancing the chronic graft versus host disease response indicating an expansion of the autoreactive B-cell pool. Screening two non-overlapping recombinants, the Sle1a.1 and Sle1a.2 intervals that cover the entire Sle1a locus, revealed that both Sle1a.1 and Sle1a.2 were necessary for the full Sle1a phenotype. Sle1a.1, and to a lesser extent Sle1a.2, significantly affected CD4(+) T-cell activation as well as Treg differentiation and function. Sle1a.2 also increased the production of autoreactive B cells. As the Sle1a.1 and Sle1a.2 intervals contain only 1 and 15 known genes, respectively, this study considerably reduces the number of candidate genes responsible for the production of autoreactive T cells. These results also show that the Sle1 locus is an excellent model for the genetic architecture of lupus, in which a major obligate phenotype results from the coexpression of multiple genetic variants with individual weak effects.

Show MeSH
Related in: MedlinePlus