The studies described here used a single-Ag model for the generation of effector cells and Tregs in vivo to explore the relationships between these cell populations. Our results indicate that differentiated Th1 effectors do not efficiently develop into Foxp3+
Tregs in vivo (). This contrasts with the ability of Th17 cells to readily develop into Tregs, at least in vitro, suggesting that Th17 cells are more plastic than differentiated Th1 or Th2 effectors (6
). Recent data have also shown that Foxp3+
Tregs can convert into Th1 (15
) and Th17 (6
) effector cells in vivo. Taken together, the conclusion of these studies is that populations of differentiated T cells vary considerably in their plasticity and interconvertibility.
The failure of differentiated Th1 cells to convert into Tregs is likely because IFN-γ inhibits the peripheral generation of Tregs. This conclusion is supported by data showing enhanced Treg generation from IFN-γ−/−
T cells in vitro and in vivo and the ability of exogenous IFN-γ to decrease Treg recovery in vitro (Figs. , ). Much of the previous work on the effects of IFN-γ on Treg development have relied on in vitro systems and have given contradictory results. Some groups have shown that IFN-γ can inhibit Treg generation or function (16
), but other studies show that IFN-γ can actually enhance generation and function (18
). Our studies are the first to show that IFN-γ made by one T cell population can inhibit the generation of Tregs from the same population in response to prolonged Ag encounter in vivo. It has been suggested that the suppressive effect of IFN-γ is related to cell death induced by reactive oxygen species (16
), our studies show that IFN-γ has only a modest effect on total cell recoveries. It has been previously demonstrated that IFN-γ produced by Th1 effectors serves to eliminate terminally differentiated Th1 cells in vivo (20
). It is unclear if the inhibition of Treg generation is related to the ability of IFN-γ to promote death of some effector cells or inhibit their proliferation.
Our studies to assess the mechanism by which IFN-γ inhibits Treg development have shown that STAT1 but not Tbet is involved in this inhibition (). Published data suggest that STAT1-deficient mice have impaired Treg function, but the influence on the generation of Treg populations from either naive cells or effector cells was not addressed (22
). It is possible that STAT1 competes with STAT5, which is necessary for Treg maintenance, or STAT1 may function indirectly by activating a pathway that inhibits Treg development. It is also a possibility that the effect of IFN-γ and STAT1 acts directly on Foxp3 expression or on other aspects of Treg development and maintenance.
The inability of Th1 cells to develop into Tregs and the inhibitory effect of IFN-γ on Treg generation suggests that once a Th1-dominant inflammatory reaction is initiated, it will likely not be controlled by peripherally generated Tregs. This implies that the transition from inflammatory disease to Treg-mediated recovery that we see after transfer of DO11.10 cells into sOVARag−/−
recipients may not be a direct conversion of effector cells to Tregs. It is more likely that recovery is related to the death of differentiated Th1 cells (20
) followed by the generation of Tregs from uncommitted cells. It remains to be established if the same events are associated with recovery in other inflammatory reactions and in nonlymphopenic situations. Answers to these questions may reveal novel approaches for limiting the life span and activity of pathogenic effector cells and promoting the development of protective regulatory cells.