High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity
Maran L. Sprouse, … , Matthew L. Bettini, Maria Bettini
Maran L. Sprouse, … , Matthew L. Bettini, Maria Bettini
Published January 25, 2018
Citation Information: JCI Insight. 2018;3(2):e97322. https://doi.org/10.1172/jci.insight.97322.
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Research Article Immunology

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

Abstract

T cell receptor (TCR) affinity is a critical factor of Treg lineage commitment, but whether self-reactivity is a determining factor in peripheral Treg function remains unknown. Here, we report that a high degree of self-reactivity is crucial for tissue-specific Treg function in autoimmunity. Based on high expression of CD5, we identified a subset of self-reactive Tregs expressing elevated levels of T-bet, GITR, CTLA-4, and ICOS, which imparted significant protection from autoimmune diabetes. We observed that T-bet expression in Tregs, necessary for control of Th1 autoimmunity, could be induced in an IFNγ-independent fashion and, unlike in conventional T cells (Tconv), was strongly correlated with the strength of TCR signaling. The level of CD5 similarly identified human Tregs with an increased functional profile, suggesting that CD5hi Tregs may constitute an efficacious subpopulation appropriate for use in adoptive Treg therapies for treatment of inflammatory conditions. Overall, this work establishes an instrumental role of high TCR self-reactivity in driving Treg function.

Authors

Maran L. Sprouse, Marissa A. Scavuzzo, Samuel Blum, Ivan Shevchenko, Thomas Lee, George Makedonas, Malgorzata Borowiak, Matthew L. Bettini, Maria Bettini

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Figure 1

CD5 correlates with self-reactivity and marks highly functional Tregs in autoimmunity.

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CD5 correlates with self-reactivity and marks highly functional Tregs in...
(A) Representative flow plot of CD5 quartile gating. (B and C) Analysis of 7- to 12-week-old NOD.Nur77GFP female mice. An average of 9 mice from 1 experiment is shown. (B) Correlation between CD5 expression and GFP reporter of Nur77 expression in islet-infiltrating Tregs (CD4+CD3+Foxp3+). (C) Correlation between CD5 expression and InsB:9-23 tetramer staining of islet-infiltrating Tregs (CD4+CD3+Foxp3+). Gating strategy depicted in Supplemental Figure 1C. (D) Representative gating strategy for sorting Teff (CD4+CD5+GFP–) and Tregs (CD4+CD5+GFP+) from the islets of NOD.Foxp3GFP mice. (E) Diabetes incidence of NOD.Tcra–/– mice which received 16,000 Teff alone (n = 10, black line), in combination with 4,000 CD5hi Tregs (n = 8, red line), or with 4,000 CD5lo Tregs (n = 8, blue line). Mice were monitored for diabetes development for 30 weeks. Data are pooled from 2 independent experiments. (F) Frequency of Tregs in the islets of NOD.Tcra–/– recipient mice at end point. Data are pooled from 4 (CD5hi) and 8 (CD5lo) mice. Significance was determined by 1-way ANOVA with Bonferroni’s multiple-comparisons test (B and C) log-rank test (E), and Mann-Whitney U test (F). The mean ± SEM is shown. (P > 0.05), *P < 0.05, **P < 0.005, ***P < 0.0005.