Signal-transducing adaptor molecules STAM1 and STAM2 are required for T-cell development and survival.
We previously reported that the STAM family members STAM1 and STAM2 are phosphorylated on tyrosine upon stimulation with cytokines through the gammac-Jak3 signaling pathway, which is essential for T-cell development. Mice with targeted mutations in either STAM1 or STAM2 show no abnormality in T-cell development, and mice with double mutations for STAM1 and STAM2 are embryonically lethal; therefore, here we generated mice with T-cell-specific double mutations for STAM1 and STAM2 using the Cre/loxP system. These STAM1(-/-) STAM2(-/-) mice showed a significant reduction in thymocytes and a profound reduction in peripheral mature T cells. In proliferation assays, thymocytes derived from the double mutant mice showed a defective response to T-cell-receptor (TCR) stimulation by antibodies and/or cytokines, interleukin-2 (IL-2) and IL-7. However, signaling events downstream of receptors for IL-2 and IL-7, such as activations of STAT5, extracellular signal-regulated kinase (ERK), and protein kinase B (PKB)/Akt, and c-myc induction, were normal in the double mutant thymocytes. Upon TCR-mediated stimulation, prolonged activations of p38 mitogen-activated protein kinase and Jun N-terminal protein kinase were seen, but activations of ERK, PKB/Akt, and intracellular calcium flux were normal in the double mutant thymocytes. When the cell viability of cultured thymocytes was assessed, the double mutant thymocytes died more quickly than controls. These results demonstrate that the STAMs are indispensably involved in T-cell development and survival in the thymus through the prevention of apoptosis but are dispensable for the proximal signaling of TCR and cytokine receptors.
Yamada
Mitsuhiro
M
Department of Microbiology and Immunology, Tohoku University School of Medicine, Sendai 980-8575, Japan.
Ishii
Naoto
N
Asao
Hironobu
H
Murata
Kazuko
K
Kanazawa
Chieko
C
Sasaki
Hidetada
H
Sugamura
Kazuo
K
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002470:Cell Survival / Q000502:physiology*; D056827:Endosomal Sorting Complexes Required for Transport; D005434:Flow Cytometry; D018390:Gene Targeting; D020287:In Situ Nick-End Labeling; D007376:Interleukin-2 / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D056827:Endosomal Sorting Complexes Required for Transport; D007376:Interleukin-2; D015851:Interleukin-7; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011948:Receptors, Antigen, T-Cell; D018121:Receptors, Cytokine; C491648:Stam protein, mouse; C491646:Stam2 protein, mouse