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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 induced a higher spontaneous proliferation and activation in CD4+ T cells, but only Sle1a.1 was associated with higher ICOS expression. A–B.In vivo BrdU incorporation shown in representative FACS plots and their quantitation. C. CD69 expression. D. CD44lo CD62L+ naïve/CD44hi CD62L− memory CD4+ ratio. E. ICOS expression. A–C shows 2–3 month old mice and D–E 8–12 month-old mice. *: p < 0.05; **: p < 0.01.
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Figure 4: Both Sle1a.1 and Sle1a.2 induced a higher spontaneous proliferation and activation in CD4+ T cells, but only Sle1a.1 was associated with higher ICOS expression. A–B.In vivo BrdU incorporation shown in representative FACS plots and their quantitation. C. CD69 expression. D. CD44lo CD62L+ naïve/CD44hi CD62L− memory CD4+ ratio. E. ICOS expression. A–C shows 2–3 month old mice and D–E 8–12 month-old mice. *: p < 0.05; **: p < 0.01.

Mentions: Sle1a expression significantly increases CD4+ T cell proliferation and activation,18 including ICOS expression.20 Expression of either Sle1a.1 or Sle1a.2 significantly increased spontaneous in vivo proliferation of the CD4+ T cells (Fig. 4A and B). This difference was observed as early as 2–3 month old, which most likely indicates a primary defect. Moreover, no difference was observed for B cell proliferation (data not shown), indicating that it does not correspond to a generalized lymphoproliferation. Increased activation was also detected in both Sle1a.1 and Sle1a.2 CD4+ T cells, with increased CD69 expression at either 2–3 month old (Fig. 4C) or 8–12 month old (data not shown), and expanded CD44hi CD62L− memory over CD44lo CD62L+ naïve CD4+ T cells in the older mice (Fig. 4D). For each of these phenotypes, the results obtained with Sle1a were similar to either that of Sle1a.1 or Sle1a.2, indicating that the two sub-loci did not have an additive effect. Increased ICOS expression however only mapped to Sle1a.1 (Fig. 4E). These results clearly show that both sub-loci contribute to increased CD4+ T cell proliferation and general activation, and that in addition, Sle1a.1 up-regulates ICOS expression.


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 induced a higher spontaneous proliferation and activation in CD4+ T cells, but only Sle1a.1 was associated with higher ICOS expression. A–B.In vivo BrdU incorporation shown in representative FACS plots and their quantitation. C. CD69 expression. D. CD44lo CD62L+ naïve/CD44hi CD62L− memory CD4+ ratio. E. ICOS expression. A–C shows 2–3 month old mice and D–E 8–12 month-old mice. *: p < 0.05; **: p < 0.01.
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Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2958247&req=5

Figure 4: Both Sle1a.1 and Sle1a.2 induced a higher spontaneous proliferation and activation in CD4+ T cells, but only Sle1a.1 was associated with higher ICOS expression. A–B.In vivo BrdU incorporation shown in representative FACS plots and their quantitation. C. CD69 expression. D. CD44lo CD62L+ naïve/CD44hi CD62L− memory CD4+ ratio. E. ICOS expression. A–C shows 2–3 month old mice and D–E 8–12 month-old mice. *: p < 0.05; **: p < 0.01.
Mentions: Sle1a expression significantly increases CD4+ T cell proliferation and activation,18 including ICOS expression.20 Expression of either Sle1a.1 or Sle1a.2 significantly increased spontaneous in vivo proliferation of the CD4+ T cells (Fig. 4A and B). This difference was observed as early as 2–3 month old, which most likely indicates a primary defect. Moreover, no difference was observed for B cell proliferation (data not shown), indicating that it does not correspond to a generalized lymphoproliferation. Increased activation was also detected in both Sle1a.1 and Sle1a.2 CD4+ T cells, with increased CD69 expression at either 2–3 month old (Fig. 4C) or 8–12 month old (data not shown), and expanded CD44hi CD62L− memory over CD44lo CD62L+ naïve CD4+ T cells in the older mice (Fig. 4D). For each of these phenotypes, the results obtained with Sle1a were similar to either that of Sle1a.1 or Sle1a.2, indicating that the two sub-loci did not have an additive effect. Increased ICOS expression however only mapped to Sle1a.1 (Fig. 4E). These results clearly show that both sub-loci contribute to increased CD4+ T cell proliferation and general activation, and that in addition, Sle1a.1 up-regulates ICOS expression.

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