Altering ß Cell Antigen Exposure to Exhausted CD8+ T Cells Prevents Autoimmune Diabetes in Mice.
J Immunol
; 212(11): 1658-1669, 2024 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-38587315
ABSTRACT
Chronic destruction of insulin-producing pancreatic ß cells by T cells results in autoimmune diabetes. Similar to other chronic T cell-mediated pathologies, a role for T cell exhaustion has been identified in diabetes in humans and NOD mice. The development and differentiation of exhausted T cells depends on exposure to Ag. In this study, we manipulated ß cell Ag presentation to target exhausted autoreactive T cells by inhibiting IFN-γ-mediated MHC class I upregulation or by ectopically expressing the ß cell Ag IGRP under the MHC class II promotor in the NOD8.3 model. Islet PD-1+TIM3+CD8+ (terminally exhausted [TEX]) cells were primary producers of islet granzyme B and CD107a, suggestive of cells that have entered the exhaustion program yet maintained cytotoxic capacity. Loss of IFN-γ-mediated ß cell MHC class I upregulation correlated with a significant reduction in islet TEX cells and diabetes protection in NOD8.3 mice. In NOD.TII/8.3 mice with IGRP expression induced in APCs, IGRP-reactive T cells remained exposed to high levels of IGRP in the islets and periphery. Consequently, functionally exhausted TEX cells, with reduced granzyme B expression, were significantly increased in these mice and this correlated with diabetes protection. These results indicate that intermediate Ag exposure in wild-type NOD8.3 islets allows T cells to enter the exhaustion program without becoming functionally exhausted. Moreover, Ag exposure can be manipulated to target this key cytotoxic population either by limiting the generation of cytotoxic TIM3+ cells or by driving their functional exhaustion, with both resulting in diabetes protection.
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1
Base de dados:
MEDLINE
Assunto principal:
Camundongos Endogâmicos NOD
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Linfócitos T CD8-Positivos
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Diabetes Mellitus Tipo 1
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Células Secretoras de Insulina
Limite:
Animals
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Austrália