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)

Read more

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

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.