A 10-aa-long sequence in SLP-76 upstream of the Gads binding site is essential for T cell development and function.
The adapter SLP-76 is essential for T cell development and function. SLP-76 binds to the src homology 3 domain of Lck in vitro. This interaction depends on amino acids 185-194 of SLP-76. To examine the role of the Lck-binding region of SLP-76 in T cell development and function, SLP-76(-/-) mice were reconstituted with an SLP-76 mutant that lacks amino acids 185-194. Double and single positive thymocytes from reconstituted mice were severely reduced in numbers and exhibited impaired positive selection and increased apoptosis. Peripheral T cells were also reduced in numbers, exhibited impaired phospholipase C-gamma1 and Erk phosphorylation, and failed to flux calcium, secrete IL-2, and proliferate in response to T cell antigen receptor ligation. Delayed cutaneous hypersensitivity responses and Ab responses to T cell-dependent antigen were severely impaired. These results indicate that the Lck binding region of SLP-76 is essential for T cell antigen receptor signaling and normal T cell development and function.
Kumar
Lalit
L
Division of Immunology, Children's Hospital, CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA.
Feske
Stefan
S
Rao
Anjana
A
Geha
Raif S
RS
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D017209:Apoptosis; D001665:Binding Sites; D015153:Blotting, Western; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D049109:Cell Proliferation; D003720:Densitometry; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000737:chemistry; D047468:Immunoprecipitation; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D037181:Lectins, C-Type; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D010047:Ovalbumin / Q000378:metabolism; D010081:Oxazolone / Q000494:pharmacology; D010641:Phenotype; D051966:Phospholipase C gamma / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D018909:src Homology Domains; D000099192:CD69 Antigens
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002118:Calcium; D048049:Extracellular Signal-Regulated MAP Kinases; D007074:Immunoglobulin G; D007376:Interleukin-2; D037181:Lectins, C-Type; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D010047:Ovalbumin; D010081:Oxazolone; D051966:Phospholipase C gamma; D010750:Phosphoproteins; D000099192:CD69 Antigens; C092947:SLP-76 signal Transducing adaptor proteins