In many experimental models, CD4+CD25+Foxp3+ regulatory T cells (nTreg)
have been identifi ed as key players in promoting peripheral transplantation (Tx)
tolerance. We have been focusing on therapies based on antigen-specifi c nTreg that
can control effector T cells (Teff) and prevent allograft rejection. The use of nTreg in
immunotherapeutic protocols for solid organ Tx is however limited by their overall
low numbers as well as the low precursor frequency of alloantigen cross-reactive
nTreg expected to be found in a normal individual. Moreover, although we previously
described robust protocols to generate and expand antigen-specifi c nTreg in vitro,
the process requires careful selection of highly pure nTreg and cumbersome ex-vivo
manipulations, rendering this strategy not easily applicable in clinical solid organ Tx.
In this study, we aimed to expand Treg directly in vivo and determine their suppressive
function, effi cacy and stability in promoting donor-specifi c tolerance in a stringent
murine Tx model. Our data suggest that IL-2-based therapies lead to a signifi cant
increase of Treg in vivo. The expanded Treg suppressed Teff proliferation (albeit
slightly less effi ciently than nTreg isolated from control mice) and allowed prolonged
graft survival of major MHC-mismatched skin grafts in wild-type non-lymphopenic
recipients. The expanded Treg alone were however not suffi cient to induce tolerance
in stringent experimental conditions. Rapamycin reduced the frequency of Teff
but did not impede expansion of Treg. Pro-infl ammatory stimuli hindered the
expansion of Treg and resulted in an increase in the frequency of CD4+IFN-γ+
and CD4+IL17+ T cells.
We propose that IL-2-based treatments would be an effi cient method for expanding
functional Treg in vivo without affecting other immune cell populations, thereby
favorably shifting the pool of alloreactive T cells towards regulation in response to
an allograft. However, we also highlight some potential limitations of Treg expansion
such as concomitant infl ammatory events.