IKKα is required for the homeostasis of regulatory T cells and for the expansion of both regulatory and effector CD4 T cells.
It was reported that TNF receptor type II signaling, which has the capacity to stimulate CD4+ forkhead box P3+ (Foxp3+) regulatory T cells (Tregs), activated the noncanonical NF-κB pathway in an IKKα-dependent manner. Therefore, we studied the role of IKKα in the homeostasis of Treg population. To this end, we generated a mouse strain with conditional knockout of IKKα in CD4 cells (Ikkα(f/f):CD4.Cre) that showed a >60% reduction in the number of Tregs in the thymus and peripheral lymphoid tissues, whereas the number of Foxp3- effector T cells (Teffs) remained at a normal level. The function of Tregs deficient in IKKα was examined using Rag1(-/-) mice cotransferred with naive CD4 cells (nCD4s). Although wild-type (WT) Tregs inhibited colitis induced by transfer of WT nCD4s, IKKα-deficient Tregs failed to do so, which was associated with their inability to reconstitute Rag1(-/-) mice. Furthermore, nCD4s deficient in IKKα also failed to reconstitute Rag1(-/-) mice and were defective in proliferative responses in vitro and in vivo. Thus, our study reveals a novel role of IKKα in the maintenance of a normal Treg population and in the control of expansion of CD4 T cells. These properties of IKKα may be exploited as therapeutic strategies in the treatment of major human diseases.
Basic Science Program, Leidos Biomedical Research, Incorporated, Laboratory of Molecular Immunoregulation, and State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China xchen@umac.mo oppenhej@mail.nih.gov.
Xin
X
Chen
Laboratory of Experimental Immunology, Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
Jami
J
Willette-Brown
Laboratory of Molecular Immunoregulation, and.
Xueqiang
X
Wu
Laboratory of Molecular Immunoregulation, and.
Ya
Y
Hu
Laboratory of Molecular Immunoregulation, and.
O M Zack
OM
Howard
Laboratory of Experimental Immunology, Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
Yinling
Y
Hu
Laboratory of Molecular Immunoregulation, and xchen@umac.mo oppenhej@mail.nih.gov.
Joost J
JJ
Oppenheim
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D049109:Cell Proliferation; D003092:Colitis / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006706:Homeostasis; D051550:I-kappa B Kinase / Q000378:metabolism / Q000502:physiology*; D007165:Immunosuppression Therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D013950:Thymus Gland / Q000378:metabolism
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; D011948:Receptors, Antigen, T-Cell; C064658:RAG-1 protein; D051550:I-kappa B Kinase
Foxp3; colitis; lymphopenic mouse; proliferation