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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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Related in: MedlinePlus

Map of the Idd9 congenic intervals contained in lines 905, 1565, 1566, and 1106 and the gene content of Idd9.2. Gaps in the assembly of the B6 sequence are marked.
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Figure 1: Map of the Idd9 congenic intervals contained in lines 905, 1565, 1566, and 1106 and the gene content of Idd9.2. Gaps in the assembly of the B6 sequence are marked.

Mentions: Experimental procedures were performed according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (protocol number 09–0074). Clone-4 T-cell receptor (TCR) NOD mice and NOD-CD45.2 congenic mice were previously described (5,11). Thy1.1+NOD-8.3-SCID mice were generated by intercrossing NOD-8.3 TCR transgenic mice (The Jackson Laboratory), with NOD-SCID mice (Taconic) and NOD-Thy1.1 mice (5). NOD-MrkTac mice (Taconic) and B10.D2 mice (The Scripps Research Institute breeding colony) were purchased. The NOD.B10 Idd9 congenic strain (Taconic line 905), which contains a continuous B10-derived DNA segment including type 1 diabetes–protective alleles Idd9.1, Idd9.2, and Idd9.3 (Fig. 1), has been previously described (5). The gene content of the congenic intervals present in NOD-Idd9.1 (line 1565) and NOD-Idd9.3 (line 1106) mice has been described previously (4,7), and NOD-Idd9.2 (line 1566) is depicted in Fig. 1. Idd9 (line 905) mice were intercrossed with NOD-SCID−/− mice to generate Idd9-SCID−/− mice, and NOD-Thy1.1+ mice to generate Idd9-Thy1.1+ mice.


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)

Map of the Idd9 congenic intervals contained in lines 905, 1565, 1566, and 1106 and the gene content of Idd9.2. Gaps in the assembly of the B6 sequence are marked.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874709&req=5

Figure 1: Map of the Idd9 congenic intervals contained in lines 905, 1565, 1566, and 1106 and the gene content of Idd9.2. Gaps in the assembly of the B6 sequence are marked.
Mentions: Experimental procedures were performed according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (protocol number 09–0074). Clone-4 T-cell receptor (TCR) NOD mice and NOD-CD45.2 congenic mice were previously described (5,11). Thy1.1+NOD-8.3-SCID mice were generated by intercrossing NOD-8.3 TCR transgenic mice (The Jackson Laboratory), with NOD-SCID mice (Taconic) and NOD-Thy1.1 mice (5). NOD-MrkTac mice (Taconic) and B10.D2 mice (The Scripps Research Institute breeding colony) were purchased. The NOD.B10 Idd9 congenic strain (Taconic line 905), which contains a continuous B10-derived DNA segment including type 1 diabetes–protective alleles Idd9.1, Idd9.2, and Idd9.3 (Fig. 1), has been previously described (5). The gene content of the congenic intervals present in NOD-Idd9.1 (line 1565) and NOD-Idd9.3 (line 1106) mice has been described previously (4,7), and NOD-Idd9.2 (line 1566) is depicted in Fig. 1. Idd9 (line 905) mice were intercrossed with NOD-SCID−/− mice to generate Idd9-SCID−/− mice, and NOD-Thy1.1+ mice to generate Idd9-Thy1.1+ mice.

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