Deletion of Irf4 in T Cells Suppressed Autoimmune Uveitis and Dysregulated Transcriptional Programs Linked to CD4+ T Cell Differentiation and Metabolism.

Minkyung Kang,Jin Kyeong Choi,Hyun-Su Lee,Cheng-Rong Yu,Charles E Egwuagu

doi:10.3390/ijms22052775

Abstract

Interferon regulatory factor-4 (IRF4) and IRF8 regulate differentiation, growth and functions of lymphoid and myeloid cells. Targeted deletion of irf8 in T cells (CD4-IRF8KO) has been shown to exacerbate colitis and experimental autoimmune uveitis (EAU), a mouse model of human uveitis. We therefore generated mice lacking irf4 in T cells (CD4-IRF4KO) and investigated whether expression of IRF4 by T cells is also required for regulating T cells that suppress autoimmune diseases. Surprisingly, we found that CD4-IRF4KO mice are resistant to EAU. Suppression of EAU derived in part from inhibiting pathogenic responses of Th17 cells while inducing expansion of regulatory lymphocytes that secrete IL-10 and/or IL-35 in the eye and peripheral lymphoid tissues. Furthermore, CD4-IRF4KO T cells exhibit alterations in cell metabolism and are defective in the expression of two Ikaros zinc-finger (IKZF) transcription factors (Ikaros, Aiolos) that are required for lymphocyte differentiation, metabolism and cell-fate decisions. Thus, synergistic effects of IRF4 and IkZFs might induce metabolic reprogramming of differentiating lymphocytes and thereby dynamically regulate relative abundance of T and B lymphocyte subsets that mediate immunopathogenic mechanisms during uveitis. Moreover, the diametrically opposite effects of IRF4 and IRF8 during EAU suggests that intrinsic function of IRF4 in T cells might be activating proinflammatory responses while IRF8 promotes expansion of immune-suppressive mechanisms.

Highlights

The interferon regulatory factor (IRF) family of transcription factors is comprised of nine members that play critical roles in regulating cell growth and development [1,2]
DNA of mice derived from mating CD4-Cre and irf4fl/fl mouse strains (C57BL/6J background) identified the CD4-Cre/IRF4fl/fl (CD4-IRF4KO) mouse strain lacking irf4 in T cells (Figure 1A)
Mating, and for all experiments described here, the phenotype was confirmed by Western blot analysis showing that the CD4-IRF4KO T cells did not express Interferon regulatory factor-4 (IRF4) (Figure 1B, left panel)

Summary

Introduction

The interferon regulatory factor (IRF) family of transcription factors is comprised of nine members that play critical roles in regulating cell growth and development [1,2]. IRF4 and IRF8 are closely related and functionally distinct from other IRFs by the relatively low binding affinity of their DBD to the core 50 GAAA-30 of the ISRE motif [4]. Both factors regulate gene transcription by interacting with. POU. or AP-1 factors FOS/JUN and the basic leucine zipper transcription factor ATF-like (BATF) factors These factors recruit IRF4 or IRF8 to ETS-IRF composite motifs (EICE) or AP-1/BATF-IRF composite elements (AICEs) of target genes [5,6,7,8,9]. The role of IRF4 or IRF8 in lymphocyte development and effector functions suggest that they are potential therapeutic targets for modulating immune responses during autoimmune diseases

Methods

Results

Conclusion