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Idd9.2 and Idd9.3 protective alleles function in CD4+ T-cells and nonlymphoid cells to prevent expansion of pathogenic islet-specific CD8+ T-cells.

Hamilton-Williams EE, Wong SB, Martinez X, Rainbow DB, Hunter KM, Wicker LS, Sherman LA - Diabetes (2010)

Bottom Line: Interestingly, the Idd9.1 region, which provides significant protection from disease, did not prevent the expansion of autoreactive CD8(+) T-cells.Idd9 protective alleles are associated with reduced expansion of IGRP-specific CD8(+) T-cells.Protective alleles in the Idd9.2 congenic subregion are required for the maximal reduction of islet-specific CD8(+) T-cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, USA.

ABSTRACT

Objective: Multiple type 1 diabetes susceptibility genes have now been identified in both humans and mice, yet mechanistic understanding of how they impact disease pathogenesis is still minimal. We have sought to dissect the cellular basis for how the highly protective mouse Idd9 region limits the expansion of autoreactive CD8(+) T-cells, a key cell type in destruction of the islets.

Research design and methods: We assess the endogenous CD8(+) T-cell repertoire for reactivity to the islet antigen glucose-6-phosphatase-related protein (IGRP). Through the use of adoptively transferred T-cells, bone marrow chimeras, and reconstituted severe combined immunodeficient mice, we identify the protective cell types involved.

Results: IGRP-specific CD8(+) T-cells are present at low frequency in the insulitic lesions of Idd9 mice and could not be recalled in the periphery by viral expansion. We show that Idd9 genes act extrinsically to the CD8(+) T-cell to prevent the massive expansion of pathogenic effectors near the time of disease onset that occurs in NOD mice. The subregions Idd9.2 and Idd9.3 mediated this effect. Interestingly, the Idd9.1 region, which provides significant protection from disease, did not prevent the expansion of autoreactive CD8(+) T-cells. Expression of Idd9 genes was required by both CD4(+) T-cells and a nonlymphoid cell to induce optimal tolerance.

Conclusions: Idd9 protective alleles are associated with reduced expansion of IGRP-specific CD8(+) T-cells. Intrinsic expression of protective Idd9 alleles in CD4(+) T-cells and nonlymphoid cells is required to achieve an optimal level of tolerance. Protective alleles in the Idd9.2 congenic subregion are required for the maximal reduction of islet-specific CD8(+) T-cells.

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The frequency of naturally occurring naive and activated phenotype CD4+ cells differs between NOD and Idd9 mice. Spleens of female 8- to 10-week-old mice were analyzed for expression of CD4, CD62L, and CD44 by flow cytometry. A: Representative FACS plots. B: Frequency of CD4+CD62L+CD44− naive cells. C: Frequency of CD4+CD62L−CD44+ activated phenotype cells. Three pooled experiments are shown. Horizontal line depicts mean value. Groups compared by Student t test. A: NOD (48.5 ± 6.6%) vs. Idd9 (58.4 ± 6.1%), P = 0.0009 (**). NOD vs. Idd9.3 (56.4 ± 8.1%), P = 0.02 (*). B: NOD (19.4 ± 3.3%) vs. Idd9 (15.4 ± 22%), P = 0.002 (**), NOD vs. Idd9.2 (16.6 ± 1.5%), P = 0.04 (*) (mean ± SD).
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Figure 8: The frequency of naturally occurring naive and activated phenotype CD4+ cells differs between NOD and Idd9 mice. Spleens of female 8- to 10-week-old mice were analyzed for expression of CD4, CD62L, and CD44 by flow cytometry. A: Representative FACS plots. B: Frequency of CD4+CD62L+CD44− naive cells. C: Frequency of CD4+CD62L−CD44+ activated phenotype cells. Three pooled experiments are shown. Horizontal line depicts mean value. Groups compared by Student t test. A: NOD (48.5 ± 6.6%) vs. Idd9 (58.4 ± 6.1%), P = 0.0009 (**). NOD vs. Idd9.3 (56.4 ± 8.1%), P = 0.02 (*). B: NOD (19.4 ± 3.3%) vs. Idd9 (15.4 ± 22%), P = 0.002 (**), NOD vs. Idd9.2 (16.6 ± 1.5%), P = 0.04 (*) (mean ± SD).

Mentions: One way in which dominant tolerance may be implemented is via regulatory T-cells that may be increased in number or function. We did not observe any difference in the frequency or number of regulatory T-cells between Idd9 and NOD mice (supplementary Fig. 6). We did, however, find a notable change in the ratio of naive to effector phenotype CD4+ T-cells between the two strains (Fig. 8). NOD mice had fewer naive cells and increased effector cells than Idd9 mice as assessed by staining for CD62L and CD44.


Idd9.2 and Idd9.3 protective alleles function in CD4+ T-cells and nonlymphoid cells to prevent expansion of pathogenic islet-specific CD8+ T-cells.

Hamilton-Williams EE, Wong SB, Martinez X, Rainbow DB, Hunter KM, Wicker LS, Sherman LA - Diabetes (2010)

The frequency of naturally occurring naive and activated phenotype CD4+ cells differs between NOD and Idd9 mice. Spleens of female 8- to 10-week-old mice were analyzed for expression of CD4, CD62L, and CD44 by flow cytometry. A: Representative FACS plots. B: Frequency of CD4+CD62L+CD44− naive cells. C: Frequency of CD4+CD62L−CD44+ activated phenotype cells. Three pooled experiments are shown. Horizontal line depicts mean value. Groups compared by Student t test. A: NOD (48.5 ± 6.6%) vs. Idd9 (58.4 ± 6.1%), P = 0.0009 (**). NOD vs. Idd9.3 (56.4 ± 8.1%), P = 0.02 (*). B: NOD (19.4 ± 3.3%) vs. Idd9 (15.4 ± 22%), P = 0.002 (**), NOD vs. Idd9.2 (16.6 ± 1.5%), P = 0.04 (*) (mean ± SD).
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Figure 8: The frequency of naturally occurring naive and activated phenotype CD4+ cells differs between NOD and Idd9 mice. Spleens of female 8- to 10-week-old mice were analyzed for expression of CD4, CD62L, and CD44 by flow cytometry. A: Representative FACS plots. B: Frequency of CD4+CD62L+CD44− naive cells. C: Frequency of CD4+CD62L−CD44+ activated phenotype cells. Three pooled experiments are shown. Horizontal line depicts mean value. Groups compared by Student t test. A: NOD (48.5 ± 6.6%) vs. Idd9 (58.4 ± 6.1%), P = 0.0009 (**). NOD vs. Idd9.3 (56.4 ± 8.1%), P = 0.02 (*). B: NOD (19.4 ± 3.3%) vs. Idd9 (15.4 ± 22%), P = 0.002 (**), NOD vs. Idd9.2 (16.6 ± 1.5%), P = 0.04 (*) (mean ± SD).
Mentions: One way in which dominant tolerance may be implemented is via regulatory T-cells that may be increased in number or function. We did not observe any difference in the frequency or number of regulatory T-cells between Idd9 and NOD mice (supplementary Fig. 6). We did, however, find a notable change in the ratio of naive to effector phenotype CD4+ T-cells between the two strains (Fig. 8). NOD mice had fewer naive cells and increased effector cells than Idd9 mice as assessed by staining for CD62L and CD44.

Bottom Line: Interestingly, the Idd9.1 region, which provides significant protection from disease, did not prevent the expansion of autoreactive CD8(+) T-cells.Idd9 protective alleles are associated with reduced expansion of IGRP-specific CD8(+) T-cells.Protective alleles in the Idd9.2 congenic subregion are required for the maximal reduction of islet-specific CD8(+) T-cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, USA.

ABSTRACT

Objective: Multiple type 1 diabetes susceptibility genes have now been identified in both humans and mice, yet mechanistic understanding of how they impact disease pathogenesis is still minimal. We have sought to dissect the cellular basis for how the highly protective mouse Idd9 region limits the expansion of autoreactive CD8(+) T-cells, a key cell type in destruction of the islets.

Research design and methods: We assess the endogenous CD8(+) T-cell repertoire for reactivity to the islet antigen glucose-6-phosphatase-related protein (IGRP). Through the use of adoptively transferred T-cells, bone marrow chimeras, and reconstituted severe combined immunodeficient mice, we identify the protective cell types involved.

Results: IGRP-specific CD8(+) T-cells are present at low frequency in the insulitic lesions of Idd9 mice and could not be recalled in the periphery by viral expansion. We show that Idd9 genes act extrinsically to the CD8(+) T-cell to prevent the massive expansion of pathogenic effectors near the time of disease onset that occurs in NOD mice. The subregions Idd9.2 and Idd9.3 mediated this effect. Interestingly, the Idd9.1 region, which provides significant protection from disease, did not prevent the expansion of autoreactive CD8(+) T-cells. Expression of Idd9 genes was required by both CD4(+) T-cells and a nonlymphoid cell to induce optimal tolerance.

Conclusions: Idd9 protective alleles are associated with reduced expansion of IGRP-specific CD8(+) T-cells. Intrinsic expression of protective Idd9 alleles in CD4(+) T-cells and nonlymphoid cells is required to achieve an optimal level of tolerance. Protective alleles in the Idd9.2 congenic subregion are required for the maximal reduction of islet-specific CD8(+) T-cells.

Show MeSH
Related in: MedlinePlus