Emerging Roles of ADAP, SKAP55, and SKAP-HOM for Integrin and NF-κB Signaling in T cells

Abstract

T cells are key mediators of cell-mediated immunity. Their functions and proliferation result from T cell-specific receptor signaling (TCR/CD28) that activates the NF-κB, NFAT, Ras-MAPK, and PI3K-Akt pathways. Their development and activation also involve a complex array of signaling pathways that regulate gene expression networks, including signaling of mTOR, Notch, Wnt, Hedgehog, TGF-β, and toll-like receptors. Furthermore, recent discoveries have provided two molecular hallmarks of potential generality: miRNA patterns and polycomb-mediated epigenetic reprogramming, which can strongly coordinate the balance between molecular networks in lymphocytes. Their deregulation apparently causes T cell disorders, such as T cell acute lymphoblastic leukemia (T-ALL), and human T cell leukemia virus (HTLV-1)-induced adult T cell leukemia (ATL). This review continues with a description of our understanding of crosstalk among the signaling pathways, which contribute to the highly orchestrated development of T cell fate specification under both normal physiological and pathological conditions.

Negative Regulation of Memory Phenotype CD8 T Cell Conversion by Adhesion and Degranulation–Promoting Adapter Protein

“…Itk inducibly binds SLP76-pY145 after TCR signaling, which may explain why the SLP-76:Y145F mutation phenocopies Itk-deficient animals (26). Although ADAP also inducibly associates with SLP-76 (9), we did not find evidence that the increased frequency of MP CD8 T cells in ADAP-deficient mice was due to an IL-4-dependent mechanism in the thymus. Our results are also consistent with the findings that the significant developmental defects in conventional T cells and NKT cells in SLP-76:Y145F and Itk-deficient mice are not observed in ADAP-deficient mice.…”

“…Initially we sought to confirm ADAP as a positive regulator of CD8 T cells interactions with Ag-pulsed APCs, as has been documented for CD4 T cells (9). We assessed the ability of wild-type and ADAP-deficient CD8 + OT-I TCR-Tg T cells, which recognize SIINFEKL (N4) peptide in the context of MHC-I H-2K b with high affinity (23), to form stable contacts with peptide-pulsed APCs by flow cytometry.…”

“…ADAP is a multifunctional adaptor protein that coordinates the formation of signaling complexes that promote TCR-mediated activation of integrins, as well as activation of the NF-κB and JNK signaling pathways (9). The expression of ADAP is restricted to cells of hematopoietic origin, including conventional CD4 and CD8 T cells and unconventional thymocytes, but is not expressed in B cell lineage cells after the Pro-B stage (10).…”

Adhesion- and Degranulation-Promoting Adapter Protein Promotes CD8 T Cell Differentiation and Resident Memory Formation and Function during an Acute Infection

“…Naïve T cell contact with cognate antigen initiates TCR-signaling events that culminate in increased adhesion of the T cell to the APC and initiation of transcriptional pathways (8, 9). Reduced TCR signaling (10, 11), or reduced T-APC interactions (12) prevents effective priming and results in reduced cytotoxic T lymphocyte (CTL) functions and altered memory generation.…”

“…ADAP positively regulates both T-APC interactions and NF-κB and JNK transcriptional pathways (9, 13–17). A fraction of ADAP is constitutively associated with Src kinase-associated phosphoprotein of 55 kDa (SKAP55) (18).…”