T Cell Islet Accumulation in Type 1 Diabetes Is a Tightly Regulated, Cell-Autonomous Event

Abstract

SUMMARY Type I diabetes is a T cell-mediated autoimmune disease, characterized by lymphocytic infiltration of the pancreatic islets. It is currently thought that islet antigen-specificity is not a requirement for islet entry and that diabetogenic T cells can recruit a heterogeneous bystander T cell population. We tested this assumption directly by generating TCR retrogenic mice expressing two different T cell populations. By combining diabetogenic and non-diabetogenic and/or non-autoantigen specific T cells, we demonstrate that bystander T cells cannot accumulate in the pancreatic islets. Autoantigen specific T cells which accumulate in islets, but do not cause diabetes, were also unaffected by the presence of diabetogenic T cells. Additionally, 67% of TCRs cloned from NOD islet-infiltrating CD4+ T cells were able to mediate cell-autonomous islet infiltration and/or diabetes when expressed in retrogenic mice. Therefore islet entry/accumulation appears to be a cell-autonomous and tightly-regulated event and is governed by islet antigen specificity.

Anti-coreceptor therapy drives selective T cell egress by suppressing inflammation-dependent chemotactic cues

“…In contrast, CXCL13 expression, which is inhibited by IFN-γ, was increased ~5-fold at 6 hours after YTS and then returned to basal levels. Expression of CCL2, 3,4,5,19, and 21 was also reduced within 24 hours following coreceptor therapy (Supplemental Figure 2). These results demonstrate that rapid suppression of T cell cytokine production, and dampening of the chemotactic milieu of the islets marked by reduced CXCL9 and 10 as well as CC-family chemokine expression, precede coreceptor therapy-induced purging.…”

“…Antigen stimulation plays a key role in retention of T cells within the islets (15)(16)(17)(18)(19). Furthermore, TCR signaling is required for IL2 and IFNG transcription, which is downregulated by YTS (35, 36)( Figure 2B).…”

“…Antigen stimulation is known to enhance islet T cell retention (16,19). Furthermore, suppression of TCR signaling is the most studied outcome of coreceptor ligation by Ab.…”

“…Once islet T cell residency is established, T cell receptor (TCR) signaling drives expression of proinflammatory cytokines, which further stimulates local production of chemotactic ligands (15)(16)(17)(18)(19). T cell-derived IFN-γ for instance, upregulates CXCL9 and CXCL10 production by islet-resident cells, including β cells, resulting in further recruitment of pathogenic CXCR3 + T H 1 cells, and innate effectors (20)(21)(22).…”

In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8+T cell inflammation

“…Rather, our data strongly argue that, in the absence of cognate pMHC, nonspecifically recruited CD8 + T cells cannot effectively compete with cognate T cell specificities for occupation of space. Recent studies in dual TCR retrogenic, sublethally irradiated bone marrow chimeras coexpressing T1D-relevant and irrelevant MHC class II-restricted autoreactive CD4 + T cell specificities in NOD.scid hosts suggest that naive CD4 + T cells may also require local engagement of cognate pMHC for recruitment to noninflamed islets (32). However, whether bystander naive and/or activated CD4 + T cells can home to inflamed islets, particularly in a model of spontaneous polyclonal inflammation such as the one described herein, remains to be determined.…”