HIV-1 Nef: a multifaceted modulator of T cell receptor signaling

Development, proliferation and immune functions of T-lymphocytes are regulated by their activation state [1]. In concert with co-stimulatory signals, T-cell activation is primarily governed by engagement of surface exposed T-Cell Antigen Receptor (TCR) complexes with Major Histocompatibility Complex (MHC) bound peptides on antigen-presenting cells (APC). These interactions occur physiologically in the context of stable cell-cell contacts referred to as immunological synapse (IS) and trigger a broad range of downstream signaling events including sequential tyrosine phosphorylation cascades, rapid elevation of intracellular calcium flux and dynamic F-actin remodeling [2-11]. These plasma membrane–associated and cytoplasmic events are transmitted to the nucleus by activation and/or import of transcription factors that launch specific transcriptional profiles characteristic for activated T-cells, including induced expression of the T-cell survival cytokine interleukin 2 (IL-2).TCR signaling in CD4+ T-cells is initiated by the interaction of the TCR α,β subunits with peptide-loaded MHC-II causing spatial rearrangements of the multi-subunit TCR complex. As one result of peptide loading, the cytoplasmic TCR zeta chain undergoes conformational changes to expose immunoreceptor tyrosine-based activation motifs (ITAMs), which become subsequently phosphorylated by the Src family kinase Lck (lymphocyte-specific protein tyrosine kinase) [12]. Phospho-ITAMs recruit the downstream kinase ZAP-70 (zeta chain associated protein of 70 kDa), which is also phosphorylated and activated by Lck [10,13,14]. Active ZAP-70 now initiates a cascade of phosphorylation events, with the most important ZAP-70 phosphorylation substrates being the trans-membrane adapter protein LAT (linker for the activation of T-cells) and the cytosolic adapter protein SLP-76 (Src homology 2 (SH2) domain–containing leukocyte phosphoprotein of 76 kD) [11,13,15-18]. These two adapters form the backbone of a signaling c