CARMA1 Regulation of Regulatory T Cell Development Involves Modulation of Interleukin-2 Receptor Signaling

Andrew Joon Lee,Xuefeng Wu,Hanyin Cheng,Xiaofei Zhou,Xuhong Cheng,Shao-Cong Sun

doi:10.1074/jbc.m109.095190

Abstract

T cell receptor-stimulated NF-kappaB activation requires CARMA1 and is negatively regulated by the deubiquitinase CYLD. Recent studies suggest that CARMA1 regulates regulatory T cell (Treg) development, although the role of NF-kappaB in this event is incompletely understood. We show that CYLD deficiency causes constitutive NF-kappaB activation in thymocytes, which is associated with enhanced frequency of Treg cells. The NF-kappaB activation in CYLD-deficient thymocytes is independent of CARMA1, because the NF-kappaB activation was also detected in CYLD/CARMA1 double knock-out thymocytes. Interestingly, although loss of CYLD causes NF-kappaB activation in the CARMA1-deficient thymocytes, the CYLD deficiency fails to rescue the defect of CARMA1 knock-out mice in Treg development. Furthermore, inhibition of canonical NF-kappaB by an IkappaBalpha transgene only partially inhibits Treg development. We demonstrate that CARMA1 regulates IL-2 receptor signaling and controls the IL-2-stimulated maturation of Treg precursors to mature Tregs. These results suggest that the role of CARMA1 in Treg regulation involves both NF-kappaB activation and IL-2 receptor signaling.

Highlights

Despite significant research efforts directed at understanding the process of Treg development, the underlying mechanism is still incompletely understood
Because CARMA1 is essential for T cell receptor (TCR)-stimulated NF-␬B activation, the NF-␬B activity should be at least partially reduced in the double knock-out (dKO) thymocytes if the TCR signaling is involved
Potent constitutive NF-␬B activity was detected in the CYLD/CARMA1 dKO thymocytes

Summary

Introduction

Despite significant research efforts directed at understanding the process of Treg development, the underlying mechanism is still incompletely understood. The CARMA1-deficient thymocytes had reduced expression CD4ϩCD25ϩFoxp3ϩ Treg cells in both the thymus and spleen of the IL-2 gene, as determined by real-time PCR analyses It is important to note, the the CYLD/CARMA1 dKO thymocytes was comparable to that increased Treg frequency in CYLDϪ/Ϫ mice could be due to the of the WT cells (Fig. 1C).

Results

Conclusion