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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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Expression of either Sle1a.1 or Sle1a.2 affects CD4+ functions in a cell-intrinsic manner. B6 hosts were reconstituted with B6.Thy1a and/or B6.Sle1a sub-loci (Thy1b allele) BM. Connected symbols indicate values for CD4+ T cells expressing the Thy1a (CD90.1-gated) or Thy1b (CD90.2-gated) alleles within the same mouse. Controls are represented by B6.Thy1a → B6 and B6.Sle1a.1 or B6.Sle1a.2→ B6 single-strain BM transfers. A. Percentage of CD4+ CD69+ splenocytes after stimulation with anti-CD3 and anti-CD28 for 12 h. B. Percentage of CD4+ CD25+ CD62L+ Treg splenocytes. Representative histograms showing CD69 and CD62L expression for Sle1a.1 chimeras are shown on the right. Two-tailed paired t tests: *: p<0.05, **: p<0.01, ***: p<0.001.
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Figure 7: Expression of either Sle1a.1 or Sle1a.2 affects CD4+ functions in a cell-intrinsic manner. B6 hosts were reconstituted with B6.Thy1a and/or B6.Sle1a sub-loci (Thy1b allele) BM. Connected symbols indicate values for CD4+ T cells expressing the Thy1a (CD90.1-gated) or Thy1b (CD90.2-gated) alleles within the same mouse. Controls are represented by B6.Thy1a → B6 and B6.Sle1a.1 or B6.Sle1a.2→ B6 single-strain BM transfers. A. Percentage of CD4+ CD69+ splenocytes after stimulation with anti-CD3 and anti-CD28 for 12 h. B. Percentage of CD4+ CD25+ CD62L+ Treg splenocytes. Representative histograms showing CD69 and CD62L expression for Sle1a.1 chimeras are shown on the right. Two-tailed paired t tests: *: p<0.05, **: p<0.01, ***: p<0.001.

Mentions: Sle1a expression affects multiple hematopoeitic cell compartments, but it results in intrinsically activated CD4+ T cells that do not require Sle1a expression in other cell types.20 The same mixed BM-chimera approach for Sle1a.1 and Sle1a.2 produced similar results (Fig. 7). The increased activation of CD4+ T cells (Fig. 7A) and the decreased percentage of CD4+ CD25+ CD62L+ Tregs (Fig. 7B) were again completely reproduced by Sle1a.1 or Sle1a.2 BM-derived cells, and in the mixed chimeras containing both congenic and normal CD4+ T cells, only those T cells expressing Sle1a.1 or Sle1a.2 displayed enhanced activation and a decreased proportion of CD62L+ Tregs. Interestingly, the increased level of activation and decreased level of Tregs associated with the Sle1a sub-loci were exaggerated when assessed in the lymphopenic environment of the mixed BM-chimera as compared to unmanipulated mice as shown in Fig. 4 and 5. Taken together, we conclude that expression of either Sle1a.1 or Sle1a.2 results in T cell-intrinsic phenotypes. The abnormal phenotypes are not transferable to bystander normal T cells, excluding Sle1a.1 or Sle1a.2 being mediated through a soluble factor.


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)

Expression of either Sle1a.1 or Sle1a.2 affects CD4+ functions in a cell-intrinsic manner. B6 hosts were reconstituted with B6.Thy1a and/or B6.Sle1a sub-loci (Thy1b allele) BM. Connected symbols indicate values for CD4+ T cells expressing the Thy1a (CD90.1-gated) or Thy1b (CD90.2-gated) alleles within the same mouse. Controls are represented by B6.Thy1a → B6 and B6.Sle1a.1 or B6.Sle1a.2→ B6 single-strain BM transfers. A. Percentage of CD4+ CD69+ splenocytes after stimulation with anti-CD3 and anti-CD28 for 12 h. B. Percentage of CD4+ CD25+ CD62L+ Treg splenocytes. Representative histograms showing CD69 and CD62L expression for Sle1a.1 chimeras are shown on the right. Two-tailed paired t tests: *: p<0.05, **: p<0.01, ***: p<0.001.
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Figure 7: Expression of either Sle1a.1 or Sle1a.2 affects CD4+ functions in a cell-intrinsic manner. B6 hosts were reconstituted with B6.Thy1a and/or B6.Sle1a sub-loci (Thy1b allele) BM. Connected symbols indicate values for CD4+ T cells expressing the Thy1a (CD90.1-gated) or Thy1b (CD90.2-gated) alleles within the same mouse. Controls are represented by B6.Thy1a → B6 and B6.Sle1a.1 or B6.Sle1a.2→ B6 single-strain BM transfers. A. Percentage of CD4+ CD69+ splenocytes after stimulation with anti-CD3 and anti-CD28 for 12 h. B. Percentage of CD4+ CD25+ CD62L+ Treg splenocytes. Representative histograms showing CD69 and CD62L expression for Sle1a.1 chimeras are shown on the right. Two-tailed paired t tests: *: p<0.05, **: p<0.01, ***: p<0.001.
Mentions: Sle1a expression affects multiple hematopoeitic cell compartments, but it results in intrinsically activated CD4+ T cells that do not require Sle1a expression in other cell types.20 The same mixed BM-chimera approach for Sle1a.1 and Sle1a.2 produced similar results (Fig. 7). The increased activation of CD4+ T cells (Fig. 7A) and the decreased percentage of CD4+ CD25+ CD62L+ Tregs (Fig. 7B) were again completely reproduced by Sle1a.1 or Sle1a.2 BM-derived cells, and in the mixed chimeras containing both congenic and normal CD4+ T cells, only those T cells expressing Sle1a.1 or Sle1a.2 displayed enhanced activation and a decreased proportion of CD62L+ Tregs. Interestingly, the increased level of activation and decreased level of Tregs associated with the Sle1a sub-loci were exaggerated when assessed in the lymphopenic environment of the mixed BM-chimera as compared to unmanipulated mice as shown in Fig. 4 and 5. Taken together, we conclude that expression of either Sle1a.1 or Sle1a.2 results in T cell-intrinsic phenotypes. The abnormal phenotypes are not transferable to bystander normal T cells, excluding Sle1a.1 or Sle1a.2 being mediated through a soluble factor.

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