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The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice.

Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, Yamazaki T, Azuma M, Iwai H, Khoury SJ, Auchincloss H, Sayegh MH - J. Exp. Med. (2003)

Bottom Line: Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance.By contrast, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade induced disease only in neonates.Insulitis scores were significantly higher and frequency of interferon gamma-producing GAD-reactive splenocytes was increased after PD-1-PD-L1 pathway blockade compared with controls.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Boston, MA 02115, USA.

ABSTRACT
Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1-PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon gamma-producing GAD-reactive splenocytes was increased after PD-1-PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1-PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.

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(A) PD-L1 expression in inflamed islets of NOD mice and PD-1 expression on infiltrating cells. Inflamed islets from 10-wk-old unmanipulated prediabetic female NOD mice showing negative staining with isotype control Ig, positive PD-1 staining of infiltrating cells (arrows), positive PD-L1 staining of islets, and negative PD-L2 staining (×400). (B) Injected anti–PD-L1 mAb binds to islets. Inflamed islet, from a 10-wk-old NOD mouse that developed diabetes after injection of anti–PD-L1, showing positive direct staining with anti–rat antibody (×400).
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fig5: (A) PD-L1 expression in inflamed islets of NOD mice and PD-1 expression on infiltrating cells. Inflamed islets from 10-wk-old unmanipulated prediabetic female NOD mice showing negative staining with isotype control Ig, positive PD-1 staining of infiltrating cells (arrows), positive PD-L1 staining of islets, and negative PD-L2 staining (×400). (B) Injected anti–PD-L1 mAb binds to islets. Inflamed islet, from a 10-wk-old NOD mouse that developed diabetes after injection of anti–PD-L1, showing positive direct staining with anti–rat antibody (×400).

Mentions: MHC class I–restricted CD8+ T cells play an important role in the initiation and mediation of autoimmune β cell destruction (23). CD8+ T cells are more sensitive to the PD-1–PD-L1 inhibitory pathway and costimulation through CD28 can overcome PD-1–mediated inhibition of CD4+ but not CD8+ T cell responses through IL-2 production (24). This might be of significance in diabetes where in the context of inflamed islets, autoreactive CD8+ T cells would be inactivated after encounter with MHC class I on parenchymal cells coexpressing PD-L1 (5, 25). PD-L1 expression has also been demonstrated in a variety of human cancers and tumor cell lines (16). Iwai et al. (26), in a tumor immunity model, recently demonstrated that transgenic expression of PD-L1 in tumor cells rendered them less susceptible to the specific T cell antigen receptor–mediated lysis by cytotoxic T cells. We examined the expression of PD-1, PD-L1, and PD-L2 in NOD islets in unmanipulated animals with established insulitis. No staining was seen with isotype control or anti–PD-L2 mAb. PD-1 expression was seen only on infiltrating cells in the inflamed islets, whereas PD-L1 was limited to inflamed islets from unmanipulated 10-wk-old female NOD mice (Fig. 5 A). Uninflamed islets from younger NOD mice and those from BALB/c and C57Bl/6 mice lacked PD-L1 expression. Moreover, direct staining with anti–rat antibody of inflamed islets from a mouse that developed diabetes after anti–PD-L1 mAb treatment (Fig. 5 B) confirmed the localization of PD-L1 in the inflamed islets. These findings and the fact that a significant number of 10-wk-old female NOD mice developed diabetes after a single injection of the mAbs suggests that this pathway may inhibit the function of islet-reactive T cells already present at the site of inflammation. However, in younger mice, in whom islet expression of PD-L1 was not seen, blockade of this pathway also precipitated diabetes, albeit more gradually, and increased GAD-reactive T cell frequencies were found in the spleens of anti–PD-1– and anti–PD-L1–treated mice. Thus, the PD-1 pathway may regulate effector T cells within the target tissue and within the peripheral lymphoid organs. Moreover, in the experimental autoimmune encephalomyelitis (EAE) model, the findings that PD-L2 blockade augments disease despite minimal PD-L2 expression in the brain of animals with EAE (22) provides further evidence for lymphoid compartment regulation by this pathway.


The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice.

Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, Yamazaki T, Azuma M, Iwai H, Khoury SJ, Auchincloss H, Sayegh MH - J. Exp. Med. (2003)

(A) PD-L1 expression in inflamed islets of NOD mice and PD-1 expression on infiltrating cells. Inflamed islets from 10-wk-old unmanipulated prediabetic female NOD mice showing negative staining with isotype control Ig, positive PD-1 staining of infiltrating cells (arrows), positive PD-L1 staining of islets, and negative PD-L2 staining (×400). (B) Injected anti–PD-L1 mAb binds to islets. Inflamed islet, from a 10-wk-old NOD mouse that developed diabetes after injection of anti–PD-L1, showing positive direct staining with anti–rat antibody (×400).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196083&req=5

fig5: (A) PD-L1 expression in inflamed islets of NOD mice and PD-1 expression on infiltrating cells. Inflamed islets from 10-wk-old unmanipulated prediabetic female NOD mice showing negative staining with isotype control Ig, positive PD-1 staining of infiltrating cells (arrows), positive PD-L1 staining of islets, and negative PD-L2 staining (×400). (B) Injected anti–PD-L1 mAb binds to islets. Inflamed islet, from a 10-wk-old NOD mouse that developed diabetes after injection of anti–PD-L1, showing positive direct staining with anti–rat antibody (×400).
Mentions: MHC class I–restricted CD8+ T cells play an important role in the initiation and mediation of autoimmune β cell destruction (23). CD8+ T cells are more sensitive to the PD-1–PD-L1 inhibitory pathway and costimulation through CD28 can overcome PD-1–mediated inhibition of CD4+ but not CD8+ T cell responses through IL-2 production (24). This might be of significance in diabetes where in the context of inflamed islets, autoreactive CD8+ T cells would be inactivated after encounter with MHC class I on parenchymal cells coexpressing PD-L1 (5, 25). PD-L1 expression has also been demonstrated in a variety of human cancers and tumor cell lines (16). Iwai et al. (26), in a tumor immunity model, recently demonstrated that transgenic expression of PD-L1 in tumor cells rendered them less susceptible to the specific T cell antigen receptor–mediated lysis by cytotoxic T cells. We examined the expression of PD-1, PD-L1, and PD-L2 in NOD islets in unmanipulated animals with established insulitis. No staining was seen with isotype control or anti–PD-L2 mAb. PD-1 expression was seen only on infiltrating cells in the inflamed islets, whereas PD-L1 was limited to inflamed islets from unmanipulated 10-wk-old female NOD mice (Fig. 5 A). Uninflamed islets from younger NOD mice and those from BALB/c and C57Bl/6 mice lacked PD-L1 expression. Moreover, direct staining with anti–rat antibody of inflamed islets from a mouse that developed diabetes after anti–PD-L1 mAb treatment (Fig. 5 B) confirmed the localization of PD-L1 in the inflamed islets. These findings and the fact that a significant number of 10-wk-old female NOD mice developed diabetes after a single injection of the mAbs suggests that this pathway may inhibit the function of islet-reactive T cells already present at the site of inflammation. However, in younger mice, in whom islet expression of PD-L1 was not seen, blockade of this pathway also precipitated diabetes, albeit more gradually, and increased GAD-reactive T cell frequencies were found in the spleens of anti–PD-1– and anti–PD-L1–treated mice. Thus, the PD-1 pathway may regulate effector T cells within the target tissue and within the peripheral lymphoid organs. Moreover, in the experimental autoimmune encephalomyelitis (EAE) model, the findings that PD-L2 blockade augments disease despite minimal PD-L2 expression in the brain of animals with EAE (22) provides further evidence for lymphoid compartment regulation by this pathway.

Bottom Line: Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance.By contrast, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade induced disease only in neonates.Insulitis scores were significantly higher and frequency of interferon gamma-producing GAD-reactive splenocytes was increased after PD-1-PD-L1 pathway blockade compared with controls.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Boston, MA 02115, USA.

ABSTRACT
Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1-PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon gamma-producing GAD-reactive splenocytes was increased after PD-1-PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1-PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.

Show MeSH
Related in: MedlinePlus