The healthy exocrine pancreas contains preproinsulin-specific CD8 T cells that attack islets in type 1 diabetes

Abstract

Preproinsulin (PPI) is presumably a crucial islet autoantigen found in patients with type 1 diabetes (T1D) but is also recognized by CD8+ T cells from healthy individuals. We quantified PPI-specific CD8+ T cells within different areas of the human pancreas from nondiabetic controls, autoantibody-positive donors, and donors with T1D to investigate their role in diabetes development. This spatial cellular quantitation revealed unusually high frequencies of autoreactive CD8+ T cells supporting the hypothesis that PPI is indeed a key autoantigen. To our surprise, PPI-specific CD8+ T cells were already abundantly present in the nondiabetic pancreas, thus questioning the dogma that T1D is caused by defective thymic deletion or systemic immune dysregulation. During T1D development, these cells accumulated in and around islets, indicating that an islet-specific trigger such as up-regulation of major histocompatibility complex class I might be essential to unmask beta cells to the immune system.

New Insights Into the Role of Autoreactive CD8 T Cells and Cytokines in Human Type 1 Diabetes

“…Remarkably, many CD8 T cells recognized the PPI 15-24 epitopes (15). In contrast to previous studies, where less than 1% of autoreactive CD8 T cells were detected within the peripheral blood (4, 5), frequencies in the pancreas are much higher (30-40%) (15). Besides, the majority of PPI-reactive CD8 T cells in the exocrine pancreas were positive for CD45RO, suggesting an antigen-experienced phenotype.…”

“…Notably, the study showed that many PPI 15-24 -specific CD8 T cells are present in the exocrine pancreas of healthy donors and donors with autoantibodies supporting the theory of a general leakiness of central tolerance. In T1D patients, these cells were not only enriched in the exocrine pancreas but were also present within the islets or close to the islets (15). The PPI-specific CD8 T cells significantly infiltrated insulincontaining islets suggesting a critical effector mechanism leading to beta-cell destruction.…”

“…In these cases, it appeared that early after diagnosis, the islets contained CD8 T cells specific for one particular autoantigen, whereas, in patients with long-standing T1D, those islets with insulitis showed T cells with multiple specificities. Building on these findings, Bender et al further examined the precise localization of PPI 15-24 -reactive CD8 T cells not only in the pancreas of nPOD donors with T1D but also in autoantibodypositive and healthy controls (15). Notably, the study showed that many PPI 15-24 -specific CD8 T cells are present in the exocrine pancreas of healthy donors and donors with autoantibodies supporting the theory of a general leakiness of central tolerance.…”

“…These evidence further prove that human islets could be infected with CVB, which could further drive pro-inflammatory factors and chemokines. The enrichment of autoreactive CD8 T cells near the islets suggests that they become attracted to their key antigen in insulin-containing islets during disease development (15), possibly due to the upregulation of MHC class I (30) and accumulation of target autoantigen (35). However, it is not clearly known whether MHC class I upregulation is responsible for the recruitment of autoreactive T cells or vice versa.…”

T cells accumulate in non-diabetic islets during ageing

“…These T cells may reside long-term and expand in situ as has been shown for tissue resident memory T cells in skin [ 45 ], or they could be recruited to islets throughout ageing by secreted factors or the accumulation of an antigen target. In the future, it would be interesting to compare T cell populations in the islets to the exocrine pancreas during ageing, as this could be a source of islet T cells, as was recently suggested in type 1 diabetes [ 46 ]. The correlation between the progressive increase in insulin secretion during ageing, observed in this study and others [ 34 – 37 ], and the progressive accumulation of islet T cells reported here, is intriguing.…”