Deleting the transcription factor Brg1 from Tregs impairs Treg function, resulting in lethal inflammation mimicking that in scurfy mice (EMBO, 2013). We have now found that restoring Brg1 expression in the dying adolescents (using a method we developed) rapidly resolves the inflammation and rescues the mice. Questions:
1) In the dying mice, CD4 cells in the peripheral blood are predominantly CD44hi CD62L lo (effector-like), but within a few weeks after restoring Brg1 expression, the CD4 cells become largely CD44low CD62L hi (naive). Apparently, the effector-like cells have been rapidly converted to naive cells. This is unprecedented? Worthwhile to follow up?
2) Any interesting issues you would like us to address using this system?
Happy Holidays!
Tian
Very interesting phenotype. Do you guys know whether this is an induction in hematopoesis which is giving rise to these naive Tcells? or does Brg1 simply affect the expression of CD44 and CD62L, hence leading to a naive like phenotype? Do these "naive" cells respond to the same antigen as the effector-like?
Thanks, Simon. We believe the"naive" cells are converted from the "effector" cells based on the rapidity (2 weeks) in the emergence of the former concomitant with the loss of the latter following the restoration of Brg1 expression in Tregs. We have not tested the function of these "naive" cells.
I think a mouse model of Collagen induced arthritis or MOG-induced EAE model would lend itself well to adressing these questions.
It might be worth inducing Collagen induced arthritis or MOG- induced EAE in these mice, then in a subset of the mice restore Brg1 expresssion. Then purify the "effector like" and "naive" cells and examine whether they respond to collagen restimulation or MOG peptide. There are also Flouresence conjugated antibodies that can directly recognize MOG-specific T cells. Therefore will help you identify whether your "naive" T cells are antigen specific or not.
If it was true that effector cells can turn to naive, that would be a great finding. Please at least sort effectors and then restoring Brg1 to see whether they can turn to naive.
Another, how about the role of Brg1 in Tregs: function, development, homeostasis, or stability?
Hi Simon and Ruan,
Happy New Year!
Thanks for your inputs! The arthritis and EAE experiments are indeed good ones although at this point we are focusing on the apparent conversion of effector cells to naive cells. The effector-like cells overproduce INFr when stimulated with Ion+PMA, suggesting they might be Th1 cells (EMBO, 2013). To test whether these cells can turn into naive cells, we are trying to adoptively transfer them into Brg KO mice and then restore Brg1 expression in the Tregs in the recipient mice to see if the transferred cells can become naive cells. BTW, following the restoration of Brg expression in Tregs, Tregs apparently proliferated, which should help resolve inflammation.
Regarding Ruan's question, it seems Brg KO does not affect Treg development, number or stability (EMBO, 2013)
Hi, Tian,
Great! I believe you will get interesting data from the experiments. You mentioned that Brg1 enhances Treg proliferation and homeostasis, I guess that Treg number should increase or change in function, migration or killing of effector cells. Will be happy to learn your findings.
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