TITLE

Local Autoantigen Expression as Essential Gatekeeper of Memory T-Cell Recruitment to Islet Grafts in Diabetic Hosts

AUTHOR(S)
Alkemade, Gonnie M.; Clemente-Casares, Xavier; Zhenguo Yu; Bao-You Xu; Jinguo Wang; Sue Tsai; Wright Jr., James R.; Roep, Bart O.; Santamaria, Pere
PUB. DATE
March 2013
SOURCE
Diabetes;Mar2013, Vol. 62 Issue 3, p905
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
It is generally believed that inflammatory cues can attract non-cognate, "bystander" T-cell specificities to sites of inflammation. We have shown that recruitment of naive and in vitro activated autoreactive CD8+ T cells into endogenous islets requires local auto-antigen expression. Here, we demonstrate that absence of an auto-antigen in syngeneic extrapancreatic islet grafts in diabetic hosts renders the grafts "invisible" to cognate memory (and naive) T cells. We monitored the recruitment of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)206-214-reactive CD8+ T cells into IGRP206-214-competent and IGRP206-214-deficient islet grafts in diabetic wild-type or IGRP206-214 nonobese diabetic hosts (harboring either naive and memory T cells or only naive IGRP206-214-specific T-cells, respectively). All four host--donor combinations had development of recurrent diabetes within 2 weeks. Wild-type hosts recruited IGRP206-214-specific T cells into IGRP206-214+/+ but not IGRP206-214-/- grafts. In IGRP206-214 hosts, there was no recruitment of IGRP206-214-specific T cells, regardless of donor type. Graft-derived IGRP206-214 activated naive IGRP206-214-specific T cells, but graft destruction invariably predated their recruitment. These results indicate that recurrent diabetes is exclusively driven by autoreactive T cells primed during the primary autoimmune response, and demonstrate that local antigen expression is a sine qua non requirement for accumulation of memory T cells into islet grafts. These findings underscore the importance of tackling autoreactive T-cell memory after β-cell replacement therapy.
ACCESSION #
85757128

 

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