The zinc finger transcription factor Early Growth Response 2 (Egr-2) is an intrinsic regulator of T cell tolerance and homeostasis
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Tolerance of T cells to self-antigen is crucial to prevent the development of autoimmune
disease. How self-tolerance is controlled at the transcriptional level is, however,
unknown. We discovered that the transcription factor Early Growth Response 2 (Egr-2)
was expressed by tolerant T cells, and by CD4+CD44high T cells in the absence of overt
antigen stimulation, in vivo. To investigate the roles of Egr-2 in T cells, we generated
CD2 cell specific Egr-2 deficient (Egr-2 cKO) mice. The proliferation of Egr-2 cKO
CD44high T cells in vivo was markedly increased leading to progressive accumulation as
the mice aged. By 15 months of age CD4+CD44high cells constituted the predominant T
cell population in the peripheral lymphoid organs of Egr-2 cKO mice and expressed
high levels of the activation markers CD25 and CD69. In addition to this
lymphoproliferative disorder, 15 month old Egr-2 cKO mice showed signs of lupus-like
autoimmune disease. This autoimmune syndrome was characterised by
glomerulonephritis and proteinuria, infiltration of T cells into internal organs and,
crucially, auto-antibodies directed against nuclear components; the hallmark of lupus.
We observed decreased expression of the cyclin-dependent kinase inhibitor p21cip1 in
Egr-2 cKO CD4+CD44high T cells while TCR stimulation induced IFN-γ, and, in
particular, IL-17A and IL-17F expression was markedly increased. Consistent with
these findings, we observed increased numbers of IFN-γ and IL-17 producing CD4+ T
cells in Egr-2 cKO mice. The numbers of IFN-γ and IL-17 producing CD4+ T cells
further increased as the mice aged in parallel with the gradual development of
symptoms of lupus-like disease. These results demonstrate that Egr-2 is an intrinsic
regulator of both T cell homeostasis and T cell tolerance.
Authors
Symonds, AlistairCollections
- Theses [4490]