Control of thymic T cell maturation, deletion and egress by the RNA-binding protein HuR.
HuR emerged as a posttranscriptional regulator of mRNAs involved in cellular control, stress, and immunity but its role in governing such responses remains elusive. In this study, we assessed HuR's role in the staged progression of thymic T cell differentiation by means of its genetic ablation. Mice with an early deletion of HuR in thymocytes possess enlarged thymi but display a substantial loss of peripheral T cells. We show that this discordant phenotype related to specific defects in thymic cellular processes, which demonstrated HuR's involvement in: 1) intrinsic checkpoint signals suppressing the cell cycle of immature thymocyte progenitors, 2) TCR and antigenic signals promoting the activation and positive selection of mature thymocytes, 3) antigenic and death-receptor signals promoting thymocyte deletion, and 4) chemokine signals driving the egress of postselection thymocytes to the periphery. The cellular consequences of HuR's dysfunction were underlined by the aberrant expression of selective cell cycle regulators, TCR, and death-receptor signaling components. Our studies reveal the signal-dependent context of HuR's cellular activities in thymocytes and its importance in the generation of a physiological T cell pool.
Papadaki
Olympia
O
Institute of Immunology, Biomedical Sciences Research Centre Alexander Fleming, Vari, Greece.
Milatos
Stavros
S
Grammenoudi
Sofia
S
Mukherjee
Neelanjan
N
Keene
Jack D
JD
Kontoyiannis
Dimitris L
DL
D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D018925:Chemokines; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D051379:Mice; D016601:RNA-Binding Proteins / Q000502:physiology*; D053218:Receptors, Death Domain; D013234:Stem Cells / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
D000954:Antigens, Surface; D018797:Cell Cycle Proteins; D018925:Chemokines; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D016601:RNA-Binding Proteins; D053218:Receptors, Death Domain