The human leukocyte antigen-A2 (HLA-A2)-restricted zinc transporter 8186-194(ZnT8186-194) and other islet epitopes elicit interferon-γ secretion by CD8+T cells preferentially in type 1 diabetes (T1D) patients compared with controls. We show that clonal ZnT8186-194-reactive CD8+T cells express private T cell receptors and display equivalent functional properties in T1D and healthy individuals. Ex vivo analyses further revealed that CD8+T cells reactive to ZnT8186-194and other islet epitopes circulate at similar frequencies and exhibit a predominantly naïve phenotype in age-matched T1D and healthy donors. Higher frequencies of ZnT8186-194-reactive CD8+T cells with a more antigen-experienced phenotype were detected in children versus adults, irrespective of disease status. Moreover, some ZnT8186-194-reactive CD8+T cell clonotypes were found to cross-recognize aBacteroides stercorismimotope. Whereas ZnT8 was poorly expressed in thymic medullary epithelial cells, variable thymic expression levels of islet antigens did not modulate the peripheral frequency of their cognate CD8+T cells. In contrast, ZnT8186-194-reactive cells were enriched in the pancreata of T1D patients versus nondiabetic and type 2 diabetic individuals. Thus, islet-reactive CD8+T cells circulate in most individuals but home to the pancreas preferentially in T1D patients. We conclude that the activation of this common islet-reactive T cell repertoire and progression to T1D likely require defective peripheral immunoregulation and/or a proinflammatory islet microenvironment.

Culina, S., Lalanne, A.I., Afonso, G., Cerosaletti, K., Pinto, S., Sebastiani, G., et al. (2018). Islet-reactive CD8+T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors. SCIENCE IMMUNOLOGY, 3(20), 1-15 [10.1126/sciimmunol.aao4013].

Islet-reactive CD8+T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors

Sebastiani, Guido;Nigi, Laura;Dotta, Francesco;
2018-01-01

Abstract

The human leukocyte antigen-A2 (HLA-A2)-restricted zinc transporter 8186-194(ZnT8186-194) and other islet epitopes elicit interferon-γ secretion by CD8+T cells preferentially in type 1 diabetes (T1D) patients compared with controls. We show that clonal ZnT8186-194-reactive CD8+T cells express private T cell receptors and display equivalent functional properties in T1D and healthy individuals. Ex vivo analyses further revealed that CD8+T cells reactive to ZnT8186-194and other islet epitopes circulate at similar frequencies and exhibit a predominantly naïve phenotype in age-matched T1D and healthy donors. Higher frequencies of ZnT8186-194-reactive CD8+T cells with a more antigen-experienced phenotype were detected in children versus adults, irrespective of disease status. Moreover, some ZnT8186-194-reactive CD8+T cell clonotypes were found to cross-recognize aBacteroides stercorismimotope. Whereas ZnT8 was poorly expressed in thymic medullary epithelial cells, variable thymic expression levels of islet antigens did not modulate the peripheral frequency of their cognate CD8+T cells. In contrast, ZnT8186-194-reactive cells were enriched in the pancreata of T1D patients versus nondiabetic and type 2 diabetic individuals. Thus, islet-reactive CD8+T cells circulate in most individuals but home to the pancreas preferentially in T1D patients. We conclude that the activation of this common islet-reactive T cell repertoire and progression to T1D likely require defective peripheral immunoregulation and/or a proinflammatory islet microenvironment.
2018
Culina, S., Lalanne, A.I., Afonso, G., Cerosaletti, K., Pinto, S., Sebastiani, G., et al. (2018). Islet-reactive CD8+T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors. SCIENCE IMMUNOLOGY, 3(20), 1-15 [10.1126/sciimmunol.aao4013].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1033730