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Breaking T cell tolerance to beta cell antigens by merocytic dendritic cells

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Abstract

In type 1 diabetes (T1D), a break in central and peripheral tolerance results in antigen-specific T cells destroying insulin-producing, pancreatic beta cells. Herein, we discuss the critical sub-population of dendritic cells responsible for mediating both the cross-presentation of islet antigen to CD8+ T cells and the direct presentation of beta cell antigen to CD4+ T cells. These cells, termed merocytic dendritic cells (mcDC), are more numerous in non-obese diabetic (NOD), and antigen-loaded mcDC rescue CD8+ T cells from peripheral anergy and deletion, and stimulate islet-reactive CD4+ T cells. When purified from the pancreatic lymph nodes of overtly diabetic NOD mice, mcDC can break peripheral T cell tolerance to beta cell antigens in vivo and induce rapid onset T cell-mediated T1D in young NOD mouse. Thus, the mcDC subset appears to represent the long-sought critical antigen-presenting cell responsible for breaking peripheral tolerance to beta cell antigen in vivo.

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Abbreviations

T1D:

Type 1 diabetes

Ag:

Antigen(s)

TCR:

T cell receptor

APC:

Antigen-presenting cell

DC:

Dendritic cell(s)

FLT3:

Fms-like tyrosine kinase 3

FLT3L:

FLT3 ligand

mcDC:

Merocytic dendritic cells

IKDC:

Natural killer dendritic cells

Th1/Tc1:

T helper cell type 1/T cytotoxic cell type 1

pDC:

Plasmacytoid dendritic cells

cDC:

Conventional dendritic cells

PLN:

Pancreatic lymph nodes

CLP:

Common lymphoid precursors

CMP:

Common myeloid precursors

NOD:

Non-obese diabetic

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  1. Division of Endocrinology, Department of Pediatrics, Cincinnati Children’s Research Foundation, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MLC 7021, Cincinnati, OH, 45229-3039, USA

    Jonathan D. Katz

  2. Division of Molecular Immunology, Department of Pediatrics, Cincinnati Children’s Research Foundation, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MLC 7021, Cincinnati, OH, 45229-3039, USA

    Jonathan D. Katz & Edith M. Janssen

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Correspondence to Jonathan D. Katz.

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Katz, J.D., Janssen, E.M. Breaking T cell tolerance to beta cell antigens by merocytic dendritic cells. Cell. Mol. Life Sci. 68, 2873–2883 (2011). https://doi.org/10.1007/s00018-011-0730-6

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