TCR Affinity and Tolerance Mechanisms Converge To Shape T Cell Diabetogenic Potential

Abstract

Autoreactive T cells infiltrating the target organ can possess a broad TCR affinity range. However, the extent to which such biophysical parameters contribute to T cell pathogenic potential remain unclear. In this study, we selected eight InsB9-23-specific TCRs cloned from CD4+ islet-infiltrating T cells that possessed a relatively broad range of TCR affinity to generate non-obese diabetic (NOD) TCR retrogenic mice. These TCRs exhibited a range of 2D affinities (~10−4 - 10−3 μm4) that correlated with functional readouts and responsiveness to activation in vivo. Surprisingly, both higher and lower affinity TCRs could mediate potent insulitis and autoimmune diabetes suggesting that TCR affinity does not exclusively dictate or correlate with diabetogenic potential. Both central and peripheral tolerance mechanisms selectively impinge on the diabetogenic potential of high affinity TCRs, mitigating their pathogenicity. Thus, TCR affinity and multiple tolerance mechanism converge to shape and broaden the diabetogenic T cell repertoire, potentially complicating efforts to induce broad, long-term tolerance.

Progression of Relapsing-Remitting Demyelinating Disease Does Not Require Increased TCR Affinity or Epitope Spread

“…The affinities for the polyclonal response to MOG measured throughout the course of demyelinating disease measured here are similar to those measured in the B6 model and also to affinities for MBP measured in CD4 clones derived from MS patients (14, 15). Recently, it was shown in the NOD model of autoimmune diabetes that both high and low 2D-affinity insulin-specific CD4 T cells were able to cause insulitis but higher affinity cells were more susceptible to tolerogenic mechanisms (33). In our study, roughly 30% of CD4 T cells infiltrating the CNS during acute disease are of higher affinity and are not present in the CNS during symptom remission.…”

High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity

“…While it is still unknown to what degree TCR affinity is important for Treg function, based on our previous observations, we suspect that a certain high level of self-reactivity is more important for Treg functional capacity than for Treg development. When tissue-specific autoimmune TCRs of either high or low affinity were expressed in TCR retrogenic mice, both high-and low-affinity TCRs supported Treg development (18). Remarkably, only mice expressing the high-affinity insulin-specific TCRs experienced accelerated diabetes development upon Treg deletion, which indicated a role for TCR affinity in Treg function.…”

“…portion to the strength of TCR signaling received in response to self-ligands, and it is stably maintained at a set level in the periphery (18,19). Although, CD5 is considered to be the most faithful marker of self-reactivity described to date, specifically in the Tconv population, direct correlation between CD5 and the magnitude of Treg self-reactivity in tissue autoimmunity has not been assessed (20,21 ) cells confirmed previous observations that Tregs express higher levels of CD5, indicative of their general propensity for self-reactivity (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.97322DS1) (22).…”

Central tolerance spares the private high‐avidity CD4+ T‐cell repertoire specific for an islet antigen in NOD mice

“…There are as yet no clear explanations for this finding but it may result from peripheral mechanisms of tolerance. Indeed, screening of a panel of insulin-reactive TCR showed that high-avidity T cells were more susceptible to regulatory T-cell conversion [33]. Given that regulatory T cells are not significantly expended in vivo upon priming with adjuvant or during in vitro restimulation in the absence of IL-2, these regulatory cells would not generate hybridoma.…”