Proinsulin-Specific, HLA-DQ8, and HLA-DQ8-Transdimer-Restricted CD4( ) T Cells Infiltrate Islets in Type 1 Diabetes

Vimukthi Pathiraja; Janine P Kuehlich; Peter D Campbell; Balasubramanian Krishnamurthy; Thomas Loudovaris; P Toby H Coates; Thomas C Brodnicki; Philip J O'Connell; Katherine Kedzierska; Christine Rodda; Philip Bergman; Erin Hill; Anthony W Purcell; Nadine L Dudek; Helen E Thomas; Thomas WH Kay; Stuart I Mannering

Journal article

Proinsulin-Specific, HLA-DQ8, and HLA-DQ8-Transdimer-Restricted CD4( ) T Cells Infiltrate Islets in Type 1 Diabetes

Vimukthi Pathiraja, Janine P Kuehlich, Peter D Campbell, Balasubramanian Krishnamurthy, Thomas Loudovaris, P Toby H Coates, Thomas C Brodnicki, Philip J O'Connell, Katherine Kedzierska, Christine Rodda, Philip Bergman, Erin Hill, Anthony W Purcell, Nadine L Dudek, Helen E Thomas, Thomas WH Kay, Stuart I Mannering

DIABETES | AMER DIABETES ASSOC | Published : 2015

DOI: 10.2337/db14-0858

Abstract

Type 1 diabetes (T1D) develops when insulin-secreting β-cells, found in the pancreatic islets of Langerhans, are destroyed by infiltrating T cells. How human T cells recognize β-cell-derived antigens remains unclear. Genetic studies have shown that HLA and insulin alleles are the most strongly associated with risk of T1D. These long-standing observations implicate CD4(+) T-cell responses against (pro)insulin in the pathogenesis of T1D. To dissect the autoimmune T-cell response against human β-cells, we isolated and characterized 53 CD4(+) T-cell clones from within the residual pancreatic islets of a deceased organ donor who had T1D. These 53 clones expressed 47 unique clonotypes, 8 of which ..

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University of Melbourne Researchers

Helen Thomas Author Medicine - St Vincent's Hospital

Christine Rodda Author Medical Education

Stuart Mannering Author Medicine - St Vincent's Hospital

Thomas Kay Author Medicine - St Vincent's Hospital

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Grants

Awarded by JDRF

Awarded by National Health and Medical Research Council (NHMRC)

Awarded by NHMRC

Funding Acknowledgements

S.I.M., V.P., and J.P.K. have received JDRF grant 17-2011-527. A.W.P. and N.L.D. have received JDRF project grant 17-2012-134. S.I.M. and A.W.P. have received National Health and Medical Research Council (NHMRC) grant APP1061961. S.I.M. and T.W.H.K. have received support from the Diabetes Australia Research Trust. S.I.M., T.W.H.K., H.E.T., B.K., V.P., and J.P.K. have received support from the Operational Infrastructure Support Program of the Victorian Government. T.W.H.K. and H.E.T. have received NHMRC program grant APP1037321. T.W.H.K., H.E.T., and T.L. have received JDRF/Department of Health and Aging grants, and P.T.C.H. has received a grant for islet transplantation. K.K. has received NHMRC project grant AI1008854. H.E.T. is supported by a fellowship from the NHMRC (APP1042735). K.K. is the recipient of an NHMRC CDF2 Fellowship. P.J.O. is an NHMRC senior practitioner fellow. A.W.P. is an NHMRC Senior Research Fellow.