The induction of exhaustion in IGRP-specific memory T cells is hampered by ongoing inflammation in the islets

T cell exhaustion is a dysfunctional state that has been associated with reduced disease activity in autoimmune disorders including type 1 diabetes (T1D). Hence, the induction of T cell exhaustion might be an attractive approach to impair self-reactive effector memory T cells and halt autoimmune responses in individuals with established autoimmunity.

Here, we aimed to determine whether antigen-experienced islet-reactive T cells in prediabetic mice can be stably exhausted by chronic exposure to autoantigen. To examine this, we used transgenic non-obese diabetic (NOD) mice with tetracycline-regulated expression of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) in antigen presenting cells (TII mice) and tracked IGRP-specific CD8⁺ T cells by tetramer enrichment.

Notably, antigen-experienced IGRP-specific T cells were readily detectable in TII mice expressing IGRP from 10 weeks of age, suggesting that they were refractory to cell deletion. However, these memory T cells significantly up-regulated several co-inhibitory receptors that are associated with cell exhaustion (but also with activation) in response to antigen exposure, e.g. PD-1, Tim-3 and TIGIT, and expressed less IFNg following stimulation. Nevertheless, these phenotypically exhausted cells were still able to infiltrate transplanted islets and kill IGRP peptide-loaded splenocytes in vivo. Moreover, cessation of antigen expression reversed the exhausted phenotype. These data suggest that antigen-induced exhaustion was neither complete nor stable. Interestingly, the number and cytotoxic function of IGRP-specific T cells were significantly decreased in TII mice after blockade of T cell migration by fingolimod (FTY720) treatment. Thus, the induction of stable exhaustion appears to be supported by reducing the migration of cells from the islets and lymphoid tissues.

We conclude that the induction of complete exhaustion in islet-reactive memory T cells was not achieved by chronic antigen exposure possibly because of migration of cells to and from islets with ongoing inflammation.