High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity
Maran L. Sprouse, Marissa A. Scavuzzo, Samuel Blum, Ivan Shevchenko, Thomas Lee, George Makedonas, Malgorzata Borowiak, Matthew L. Bettini, Maria Bettini
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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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 2

Both CD5hi and CD5lo Tregs can maintain T cell homeostasis.

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Both CD5hi and CD5lo Tregs can maintain T cell homeostasis. Analysis of ...
Analysis of NOD.scid recipient spleens 4 weeks after T cell transfer. (A) Mice received 5 × 105 naive Tconv alone (white), in combination with 1.25 × 105 CD5hi (top 50%) Tregs (red), or with 1.25 × 105 CD5lo (bottom 50%) Tregs (blue). Gating strategy and purity depicted in Supplemental Figure 2, C and D. Tconv expansion is based on total number of CD4+CD3+Foxp3– cells in spleens of recipient mice. An average of 3 mice from 1 experiment is shown. (B–D) Mice received 5 × 105 naive Tconv alone, in combination with 1.25 × 105 CD5hi (top 35%) Tregs (red), or with 1.25 × 105 CD5lo (bottom 35%) Tregs (blue). Gating strategy and purity shown in Supplemental Figure 2, F and G. An average of 4–5 mice from 2 experiments is shown. (B) Tconv expansion is based on total number of CD4+CD3+Foxp3– cells in spleens of recipient mice. (C) Frequency of Tregs within the CD4+CD3+ population 4 weeks after transfer. (D) CD5 expression in splenic Tregs 4 weeks after transfer. Significance was determined by 1-way ANOVA with Bonferroni’s multiple-comparisons test (A and B) and Mann-Whitney U test (C and D). The mean ± SEM is shown. (P > 0.05), **P < 0.005, ***P < 0.0005.