TRAF3 restrains regulatory T cell development by modulating IL-2 signaling (P1219)

Abstract

Abstract The signaling protein TNF receptor associated factor 3 (TRAF3) has multiple diverse effects on signaling transduction. We recently produced a new strain of T cell specific TRAF3 deficient mice (CD4CreTRAF3flox/flox (T-T3-/-)), and found that the frequency and number of Foxp3+ regulatory T cells (Treg) are increased 2-3 times compared with litter mate control mice (LMC), though total CD4+ and CD8+ T cell numbers do not change. These Treg are Helios+ and the increase is cell intrinsic. Interestingly, thymic Treg emerge as early as day 1 after birth in T-T3-/- mice, compared to day 3 after birth in LMC. Notably, the percentage of Treg precursor cells is unchanged. However, following IL-2 stimulation, TRAF3-deficient Treg precursor cells convert into Foxp3+ Treg more efficiently than those of LMC, though expression levels of IL-2 receptor components are comparable. We further found that phosphorylation of STAT5 is remarkably enhanced in TRAF3-/- Treg precursors in response to IL-2 stimulation. We also noticed that T-T3-/- conventional CD4 T cells exhibit robustly enhanced p-STAT5, but not p-ERK and p-AKT, when stimulated with IL-2. Additionally, TRAF3 deficiency affects the plasma membrane localization of T Cell Protein Tyrosine Phosphatase (TCPTP), an enzyme that plays a negative role in IL-2 signaling. Taken together, our data show for the first time that TRAF3 is an important regulator of IL-2 signaling and affects Treg development.