Abstract
Our previous study showed that TNFR2 is preferentially expressed by CD4+FoxP3+ regulatory T (Treg) cells and expression of this molecule identified the maximally suppressive Treg cells. TNFR2 is also expressed by a small fraction of CD4+FoxP3- conventional T (Tconv) cells in normal mice and its expression is up-regulated by T cell activation. Our data indicate that TNFR2 also co-stimulates Tconv cells. In this study, by using FoxP3/gfp KI mice, we showed that TNFR2 signaling did not induce FoxP3- CD4 cells to become suppressive. TNFR2 is associated with greater suppressive functions when expressed by Treg cells and is associated with greater resistance to suppression when expressed by Tconv cells, because TNFR2+ Tconv cells were potently suppressed by FoxP3+TNFR2+ Treg cells, while resisting suppression by FoxP3+TNFR2- Treg cells. Furthermore, in mice with 4T1 breast tumor and LLC, intratumoral Tconv cells expressing elevated levels of TNFR2 acquired the capacity to resist the suppression mediated by LN-derived Treg cells. However, they remained susceptible to inhibition by more suppressive tumor infiltrating Treg cells which expressed higher levels of TNFR2. Intratumoral Treg cells express more TNFR2 and they are able to overcome the inhibition-resistance of intratumoral Tconv cells, resulting in a dominant immunosuppressive tumor environment. (Funded by NCI Contract N01-CO-12400)
