HIP-55 is important for T-cell proliferation, cytokine production, and immune responses.
Engagement of the T-cell receptor (TCR) triggers a series of signaling events that lead to the activation of T cells. HIP-55 (SH3P7 or mAbp1), an actin-binding adaptor protein, interacts with and is tyrosine phosphorylated by ZAP-70, which is a crucial proximal protein tyrosine kinase for TCR signaling. HIP-55 is important for JNK and HPK1 activation induced by TCR signaling. In this study, we report the generation and characterization of HIP-55 knockout mice. We found that HIP-55 knockout mice were viable and fertile but showed decreased body weight and increased occurrence of death within the first 4 weeks after birth. The lymphoid organs in HIP-55 knockout mice showed cellularity and T-cell development comparable to that of the wild-type mice. HIP-55 knockout T cells displayed defective T-cell proliferation, decreased cytokine production, and decreased up-regulation of the activation markers induced by TCR stimulation. TCR internalization was slightly increased in HIP-55 knockout T cells. These phenotypes were accompanied by reduced immune responses, including antigen-specific antibody production and T-cell proliferation in HIP-55 knockout mice. The TCR-induced signaling events, including LAT/phospholipase Cgamma1 phosphorylation and HPK1/JNK activation, were partially defective in HIP-55 knockout T cells. These results demonstrate the importance of HIP-55 as an adaptor protein in the TCR signaling and immune system.
Han
Jin
J
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030. ttan@bcm.edu.
Shui
Jr-Wen
JW
Zhang
Xuejun
X
Zheng
Biao
B
Han
Shuhua
S
Tan
Tse-Hua
TH
D000199:Actins / Q000737:chemistry; D000483:Alleles; D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D001835:Body Weight; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007107:Immune System; D047468:Immunoprecipitation; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism / Q000502:physiology*; D008957:Models, Genetic; D009154:Mutation; D051966:Phospholipase C gamma; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry; D012313:RNA / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry; D051746:ZAP-70 Protein-Tyrosine Kinase; D018909:src Homology Domains / Q000502:physiology*
D000199:Actins; D016207:Cytokines; C117063:DBNL protein, human; D008840:Microfilament Proteins; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D012313:RNA; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse; D010738:Type C Phospholipases; D051966:Phospholipase C gamma