Background/Purpose: Acquisition of an effector phenotype is critical for Treg function in chronic inflammatory settings such as those encountered in autoimmune diseases like lupus. Although IRF4 is an essential controller of effector Tregs, the mechanisms orchestrating its function in these cells are largely unknown. In non-Tregs, IRF4 function can be modulated by interaction with DEF6 and its homologue SWAP-70. Mice lacking DEF6 and SWAP-70 (DKO mice) develop a lupus-like syndrome but display normal survival. The purpose of this study was to test the hypothesis that DEF6 and SWAP-70 restrain IRF4 activity in Tregs and that, in DKO mice, Tregs have an increased ability to become effector Tregs and thus blunt disease severity. 

Methods: FACS analysis of DKO mice was employed to systematically evaluate Treg frequencies and effector Treg phenotypes during disease development. DKO mice were crossed to Blimp1-YFP-10BiT dual reporter mice to assess expression of the Blimp1-IL10 gene module in DKO Tregs. Selective deletion of IRF4 in the Treg compartment was achieved by crossing DKO mice with Foxp3-Cre IRF4^fl/fl mice.

Results:

Unlike naïve T_H cells that express only DEF6, Tregs were found to express both DEF6 and SWAP-70. Analysis of DKO mice demonstrated that the concomitant absence of these two molecules leads to increased numbers of Tregs, which acquire an effector phenotype in a cell-intrinsic manner. In addition, DKO Tregs exhibit enhanced expression of the Blimp-1-IL-10 axis. Notably, DKO effector Tregs survive and expand as disease progresses. The expansion of DKO Tregs was associated with the upregulation of genes controlling autophagy and was found to be IRF4-dependent. Unlike the remarkable accumulation of most effector Tregs, DKO mice exhibited only a minimal expansion of T_FR cells resulting in an imbalanced T_FH/T_FR ratio over time. 

Conclusion:

This work uncovers the existence of mechanisms that, by acting on IRF4, can fine-tune the function and survival of effector Tregs and maximize the fitness of effector Tregs in chronic inflammatory conditions. These studies suggest that, despite the presence of autoimmune features such as dysregulated humoral responses, the existence of a powerful effector Treg compartment that successfully survives in an unfavorable inflammatory environment can effectively limit disease development. Such a scenario is highly relevant to human SLE whose clinical heterogeneity could be linked, at least in part, to the presence/absence of long-lived effector Tregs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/modulation-of-irf4-function-promotes-expansion-of-effector-tregs-in-lupus/