Egr3 induces a Th17 response by promoting the development of γδ T cells.
The transcription factor Early Growth Response 3 (Egr3) has been shown to play an important role in negatively regulating T cell activation and promoting T cell anergy in Th1 cells. However, its role in regulating other T helper subsets has yet to be described. We sought to determine the role of Egr3 in a Th17 response using transgenic mice that overexpress Egr3 in T cells (Egr3 TG). Splenocytes from Egr3 TG mice demonstrated more robust generation of Th17 cells even under non-Th17 skewing conditions. We found that while Egr3 TG T cells were not intrinsically more likely to become Th17 cells, the environment encountered by these cells was more conducive to Th17 development. Further analysis revealed a considerable increase in the number of γδ T cells in both the peripheral lymphoid organs and mucosal tissues of Egr3 TG mice, a cell type which normally accounts for only a small fraction of peripheral lymphocytes. Consistent with this marked increase in peripheral γδ T cells, thymocytes from Egr3 TG mice also appear biased toward γδ T cell development. Coculture of these Egr3-induced γδ T cells with wildtype CD4+ T cells increases Th17 differentiation, and Egr3 TG mice are more susceptible to bleomycin-induced lung inflammation. Overall our findings strengthen the role for Egr3 in promoting γδ T cell development and show that Egr3-induced γδ T cells are both functional and capable of altering the adaptive immune response in a Th17-biased manner. Our data also demonstrates that the role played by Egr3 in T cell activation and differentiation is more complex than previously thought.
The Sidney-Kimmel Cancer Research Center, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
Rose M
RM
Parkinson
Division of Pulmonary Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Samuel L
SL
Collins
Division of Pulmonary Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Maureen R
MR
Horton
The Sidney-Kimmel Cancer Research Center, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
Jonathan D
JD
Powell
D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D001761:Bleomycin; D002454:Cell Differentiation; D004198:Disease Susceptibility; D051776:Early Growth Response Protein 3 / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D020381:Interleukin-17 / Q000096:biosynthesis / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D060168:Thymocytes / Q000276:immunology / Q000473:pathology; D019076:Transgenes
C497369:Egr3 protein, mouse; D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta; D001761:Bleomycin; D051776:Early Growth Response Protein 3