Loss of IRF-4-binding protein leads to the spontaneous development of systemic autoimmunity.
IFN regulatory factor 4-binding (IRF-4-binding) protein (IBP) is a novel type of activator of Rho GTPases that is recruited to the immunological synapse upon TCR stimulation. Here we demonstrate that loss of IBP leads to the spontaneous development of a systemic autoimmune disorder characterized by the accumulation of effector/memory T cells and IgG+ B cells, profound hypergammaglobulinemia, and autoantibody production. Similar to human SLE, this syndrome primarily affects females. T cells from IBP-deficient mice are resistant to death in vitro as well as in vivo and exhibit selective defects in effector function. In the absence of IBP, T cells respond suboptimally to TCR engagement, as demonstrated by diminished ERK1/2 activation, decreased c-Fos induction, impaired immunological synapse formation, and defective actin polymerization. Transduction of IBP-deficient T cells with a WT IBP protein, but not with an IBP mutant lacking the Dbl-like domain required for Rho GTPase activation, rescues the cytoskeletal defects exhibited by these cells. Collectively, these findings indicate that IBP, a novel regulator of Rho GTPases, is required for optimal T cell effector function, lymphocyte homeostasis, and the prevention of systemic autoimmunity.
Fanzo
Jessica C
JC
Department of Medicine, Columbia University, New York, New York 10032, USA.
Yang
Wen
W
Jang
So Young
SY
Gupta
Sanjay
S
Chen
Qinzhong
Q
Siddiq
Ayesha
A
Greenberg
Steven
S
Pernis
Alessandra B
AB
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D020662:Guanine Nucleotide Exchange Factors; D007156:Immunologic Memory / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4
D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D050835:Interferon Regulatory Factors; D009687:Nuclear Proteins; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4; C479750:DEF6 protein, human