Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development.
Regulatory T cell (Treg) development proceeds via a two-step process in which naive CD4(+) thymocytes are first converted into CD4(+)CD25(+)CD122(+)GITR(+)Foxp3(-) Treg progenitors, followed by a second step in which IL-2 converts these Treg progenitors into CD4(+)Foxp3(+) Tregs. The costimulatory molecule CD28 is required for efficient Treg development. However, the stage at which CD28 affects Treg development remains undefined. In this article, we demonstrate that Cd28(-/-) mice lack Treg progenitors. Furthermore, the P(187)YAP motif in the cytoplasmic tail of CD28, which links CD28 to Lck activation, is required for this process. In contrast, the Y(170)MNM motif, which links CD28 to PI3K activation, is not required for Treg progenitor development. Finally, the CD28/Lck pathway was shown to activate the NF-kappaB family of transcription factors. We demonstrate that c-Rel, but not NF-kappaB1, promotes the development of Treg progenitors. Thus, a CD28/c-Rel-dependent pathway is involved in initiating Treg development.
Department of Laboratory Medicine and Pathology, The Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Kieng B
KB
Vang
Jianying
J
Yang
Antonio J
AJ
Pagán
Lin-Xi
LX
Li
Junmei
J
Wang
Jonathan M
JM
Green
Amer A
AA
Beg
Michael A
MA
Farrar
D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D000818:Animals; D018106:CD28 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D003593:Cytoplasm / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D055879:Gene Knock-In Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D020569:Proto-Oncogene Proteins c-rel / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D018106:CD28 Antigens; D007376:Interleukin-2; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D010446:Peptide Fragments; D020569:Proto-Oncogene Proteins c-rel; C073701:Nfkb1 protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)