Negative Regulation Of T Cell Activation And Function By CIN85 Adaptor Protein
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Date
2017-01
Authors
Kong, Mei Suen
Journal Title
Journal ISSN
Volume Title
Publisher
Universiti Sains Malaysia
Abstract
Antigen recognition by T cell receptor (TCR) induces intracellular signaling
cascades leading to T cell activation, subsequently inducing cellular proliferation and
various effector functions. Adaptor proteins play important roles in T cell signaling
by creating nodes to recruit signaling proteins and form signal complexes to regulate
the direction of signaling. Casitas B-lineage lymphoma (Cbl)-interacting protein of
85 kDa (CIN85) is an adaptor protein, originally identified as a Cbl-binding protein,
and was suggested to be involved in the internalization and degradation of receptors
and kinases. Nevertheless, the physiological function of CIN85 in T cells is unknown.
To understand the role of CIN85 in T cell function, T cell-specific CIN85-knockout
(KO) mice were generated and analyzed in this study. CIN85-KO naïve T cells were
found to exhibit hyper-responsiveness to TCR stimulation; i.e. significantly
increased interleukin 2 (IL-2) production, cell proliferation and alteration of
differentiation into T helper type 1 (Th1) phenotypes, suggesting that CIN85 exhibits
negative regulation in T cell activation. Analysis of signaling molecules showed that
tyrosine phosphorylation of TCR-downstream molecules, such as ζ-chain associated
protein kinase of 70 kDa (Zap70), SH2 domain-containing leukocyte protein of 76
kDa (SLP76), phospholipase C-gamma (PLCγ), c-Jun-N-terminal kinase (JNK) and
extracellular-signal-regulated kinase (ERK), were significantly enhanced in
CIN85-KO T cells. This implied that CIN85 was involved in the early TCR signaling
complex to negatively regulate T cell activation. As for T cell development,
CIN85-KO mice were found to display higher population of CD44hi
effector/memory-type T cells at the periphery, suggesting an important role of CIN85
in maintaining the homeostasis of T cells in vivo.
Description
Keywords
Negative regulation of T cell activation , function by CIN85 adaptor protein