Our study supports the concept that AK and BD are precursors of cSCC. The identification of proteome changes indicates disruption of repair, pro-apoptotic, and tumor promoting pathways. Our findings will help select targets for classification and treatment.
A T cell antigen receptor (TCR) transmembrane sequence derived peptide (CP) has been shown to inhibit T cell activation both in vitro and in vivo at the membrane level of the receptor signal transduction. To examine the effect of sugar or lipid conjugations on CP function, we linked CP to 1-aminoglucosesuccinate (GS), N-myristate (MYR), mono-di-tripalmitate (LP1, LP2, or LP3), and a lipoamino acid (LA) and examined the effects of these compounds on T cell activation in vitro and by using a rat model of adjuvant-induced arthritis, in vivo. In vitro, antigen presentation results demonstrated that lipid conjugation enhanced CP's ability to lower IL-2 production from 56.99%+/-15.69 S.D. observed with CP, to 12.08%+/-3.34 S.D. observed with LA. The sugar conjugate GS resulted in only a mild loss of in vitro activity compared to CP (82.95%+/-14.96 S.D.). In vivo, lipid conjugation retarded the progression of adjuvant-induced arthritis by approximately 50%, whereas the sugar conjugated CP, GS, almost completely inhibited the progression of arthritis. This study demonstrates that hydrophobic peptide activity is markedly enhanced in vitro and in vivo by conjugation to lipids or sugars. This may have practical applications in drug delivery and bioavailability of hydrophobic peptides.
This study examines the binding properties of a new class of immunomodulating peptides derived from the transmembrane region of the T cell antigen receptor, on model membranes using surface plasmon resonance. The di-basic "core" peptide was found to bind to both zwitterionic and anionic model membranes as well as to a T cell membrane preparation. By contrast, switching one or both of the basic residues to acidic residues led to a complete loss of binding to model membranes. In addition, the position of the charged amino acids in the sequence, the number of hydrophobic amino acids between the charged residues, and substitution of one or both basic to neutral amino acids were found to effect binding. These results when compared with in vitro T cell stimulation assays and in vivo adjuvant-induced arthritis models, showed very close correlation and confirmed the findings that amino acid charge and location may have a role in peptide activity. These initial biophysical peptide-membrane interactions are critically important and correlate well with the subsequent cellular expression and biological effect of these hydrophobic peptides. Targeting and understanding the biophysical interactions between peptides and membranes at their site of action is paramount to the description of cell function and drug design.T cells constitute an important component of our immune system and are concerned with immune surveillance and antigen recognition. Whereas this is normally a beneficial, protective effect, recognition of "self-antigens" under altered pathological states leads to autoimmune disease with deleterious consequences. The T cell antigen receptor (TCR) 1 is a cell surface multisubunit protein complex present only on T cells and involved with antigen recognition and subsequent T cell activation. The TCR consists of two clonotypic chains (TCR-␣ and -) that are noncovalently linked to CD3-⑀, -␥, -␦, and -/ invariant proteins. Two important structural features common to these chains is the presence of a single transmembrane spanning domain and the presence of charged amino acid(s) within their predicted transmembrane region. The invariant chains have a single negative charge and TCR-␣ and - have two and one positive charges, respectively. These charged amino acids influence the intracellular fate of these proteins and are critical for TCR assembly (1, 2). Following TCR cell surface expression a key event in initiating antigen-induced signal transduction is the formation of higher order oligomerization complexes between TCR, co-receptors, and accessory molecules at the cell membrane. This protein-protein-lipid interface allows a number of biochemical events to proceed rapidly commencing with tyrosine or serine/threonine phosphorylation of the TCR chains (3) that subsequently translates into T cell activation and cytokine production. The ability to inhibit pathogenic T cells by blocking the TCR by hydrophobic transmembrane-derived peptides has been the focus of our research for a number of years (4 -8).We have previously ide...
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