Abstract
Islet transplantation provides a “cure” for type 1 diabetes but is limited in part by recurrent autoimmunity mediated by β cell-specific CD4+ and CD8+ T cells. Insight into the T cell receptor (TCR) repertoire of effector T cells driving recurrent autoimmunity would aid the development of immunotherapies to prevent islet graft rejection. Accordingly, we used a multi-parameter flow cytometry strategy to assess the TCR variable β (Vβ) chain repertoires of T cell subsets involved in autoimmune-mediated rejection of islet grafts in diabetic NOD mouse recipients. Naïve CD4+ and CD8+ T cells exhibited a diverse TCR repertoire, which was similar in all tissues examined in NOD recipients including the pancreas and islet grafts. On the other hand, the effector/memory CD8+ T cell repertoire in the islet graft was dominated by one to four TCR Vβ chains, and specific TCR Vβ chain usage varied from recipient to recipient. Similarly, islet graft- infiltrating effector/memory CD4+ T cells expressed a limited number of prevalent TCR Vβ chains, although generally TCR repertoire diversity was increased compared to effector/memory CD8+ T cells. Strikingly, the majority of NOD recipients showed an increase in TCR Vβ12-bearing effector/memory CD4+ T cells in the islet graft, most of which were proliferating, indicating clonal expansion. Importantly, TCR Vβ usage by effector/memory CD4+ and CD8+ T cells infiltrating the islet graft exhibited greater similarity to the repertoire found in the pancreas as opposed to the draining renal lymph node, pancreatic lymph node, or spleen. Together these results demonstrate that effector/memory CD4+ and CD8+ T cells mediating autoimmune rejection of islet grafts are characterized by restricted TCR Vβ chain usage, and are similar to T cells that drive destruction of the endogenous islets.
Highlights
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of the insulin-secreting b cells residing in the pancreatic islets of Langerhan’s [1,2,3,4,5]
The frequency of Ki67+ T cell receptor (TCR) Vb12-expressing CD4+ Teff/mem was increased in the draining renal lymph node (RLN) compared to the spleen (Figure 6B). These findings indicate that in most NOD recipients the TCR variable b (Vb) repertoire in islet grafts is characterized by an increase in TCR Vb12 usage, which in turn is associated with elevated Vb12-specific CD4+ Teff/mem proliferation
Similar trends were observed for islet graft-infiltrating CD4+ Teff/mem where the divergence index for the TCR repertoire between the islet graft and pancreas (0.05960.02) was less than the divergence index calculated for comparisons between the islet graft versus spleen (0.1460.03), pancreatic lymph node (PLN) (0.1560.03) and RLN (0.1360.03) (Figure 7B). These results demonstrate that the distribution of Vb usage by CD4+ and CD8+ Teff/mem in grafted islets is more similar to Vb usage in the endogenous islets than that in the spleen, PLN and RLN
Summary
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of the insulin-secreting b cells residing in the pancreatic islets of Langerhan’s [1,2,3,4,5]. As b cell autoimmunity progresses, several autoantigens are targeted due to intra- and inter-molecular epitope spread, resulting in the expansion of multiple clonotypes of pathogenic b cell-specific effector T cells (Teff) [11,12,13,14,15,16,17,18] The latter is evident by a T cell receptor (TCR) repertoire marked by expression of multiple TCR variable (V) genes by islet resident T cells [19,20,21], and b cell-specific T cell clones [19,22,23,24,25,26]. Once ,80% of the b cell mass has been destroyed and/or rendered nonfunctional, hyperglycemic blood levels are achieved and the onset of overt diabetes diagnosed
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