Xenogeneic islet transplantation has been one ongoing goal for treating autoimmune Type 1 diabetes. Autoimmune diabetes involves a T cell response restricted to the host MHC molecules presenting islet-associated autoantigens. As such, autoimmunity is sometimes considered to be a special circumstance in which allogeneic (MHC-mismatched) or even xenogeneic tissues might actually be advantageous by avoiding recognition by pre-existing autoreactive T cells. However, previous reports show that CD4+ islet-specific T cells derived from non-obese diabetic (NOD) mice are capable of initiating autoimmune diabetes upon appropriate adoptive transfer, often without a requirement for CD8+ T cells or B cells. Such observations raise the question of how CD4+ T cells thought to recognize antigens in association with class II MHC antigens trigger the destruction of islet beta cells that are generally considered to be devoid of class II MHC surface expression. A large panel of NOD-derived CD4+ T cell clones recognize an epitope present on residues 9-23 of the B chain of insulin (B9-23) that is conserved among many mammalian species, including mouse, rat, porcine, and human. One such clone, PD12-4.4, shown to be pathogenic in NOD mice was tested in detail for the ability to damage rat and human islet xenografts established in immune-deficient NODscid mice. Clone PD12-4.4 mediated destruction of 8/8 rat and 5/6 human islet xenografts, despite the genetic inability of these transplants to express NOD I-Ag7 class II molecules. Moreover, destruction of rat islets was tissue-specific in that PD12-4.4 T cells destroyed islet (4/4) but not thyroid (0/4) xenografts implanted beneath opposite ends of the kidney capsule of the same recipient. In contrast, polyclonal NOD spleen cells – containing both autoreactive and xenoreactive T cells – rejected both rat islet (7/7) and thyroid (7/7) xenografts. We conclude that islet-specific CD4+ T cells can lead to overt autoimmune diabetes through an inflammatory mechanism that does not require direct T cell receptor engagement of the target islet beta cell, a process that is analogous to 'indirect' CD4 T cell recognition of allogeneic antigens presented by host MHC class II. More importantly, these results suggest that this pathway may make islet xenografts vulnerable to CD4 T cell-dependent autoimmune recognition provided that the original islet xenograft expresses the appropriate islet-associated autoantigens available for host APC acquisition and presentation.

CITATION INFORMATION: Gill R, Dale W, Crawford M. Recognition of Islet Xenografts In Vivo by Non-Obese Diabetic (NOD) Insulin-Specific CD4 T Cells. Am J Transplant. 2017;17 (suppl 3).

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