Do T lymphocytes correlate danger signals to antigen?
When a cell is infected by a virus, or becomes transformed into a malignant state, it presents clues to its disease on the outer surface of its membrane. Such clues include peptide fragments of proteins produced inside the cell; when the cell is infected by a virus, viral peptides, as well as the cell's normal peptides, are displayed on the cell's membrane as potential antigens. Infected and malignant cells also externally present special molecules that ligate NKG2D receptors on immune cells. When patrolling T lymphocytes detect the presence of both their cognate peptide antigen and NKG2D ligands on one target, they proliferate and increasingly kill other cognate target cells. The danger model of immunity recognizes NKG2D ligands as stimulators of T cell cytotoxicity, but heretofore could not explain how T cells specific to normal peptides typical of healthy host cells outside the thymus, could avoid activation by danger signals on diseased cells. The problem is that T cells specific to host-peptides are also stimulated when those peptides are by chance also displayed on diseased cells displaying NKG2D ligands. However, if T cells predicated their cytotoxicity not only on the presence of their cognate antigen found in conjunction with danger signals, but also on the absence of their cognate antigen on cells not presenting danger signals, then only T cells specific for disease antigens would become activated. Since Fas display is correlated with viral or malignant transformation, it may be a danger-signal like NKG2D ligands. T cells which encounter Fas on malignant, cognate cells, increasingly bind Fas on healthy bystander cells not displaying cognate antigens. Perhaps such healthy bystander cells provide T cells with reference-levels of danger-signals for local tissue cells, allowing T cells to select between tolerance and cytotoxic reaction to their cognate antigen, as they circulate in the periphery. This paper will analyze cytotoxicity assays that show that T cells challenge syngeneic, non-cognate bystanders with Fas ligand (FasL), and why syngeny is a requirement for danger-reference cells. Some heretofore unexplained effects of superantigens will be suggested to be due to their obstruction of reference-target detection. This paper will also suggest that established tumors often evolve a subpopulation of high-danger-signal, low tumor-antigen cells that protect the tumor against T cells; that characteristics of dendritic cells (DC) complement the danger sensing of T cells; and that DC may also use quantitatively comparative, self-referential, danger-correlation measurements to recognize transformed cells interspersed among healthy host tissue cells.
Forden
Chris
C
chrisaforden@yahoo.com
D000818:Animals; D000941:Antigens / Q000737:chemistry*; D003713:Dendritic Cells / Q000166:cytology; D053222:Fas Ligand Protein; D006801:Humans; D007108:Immune Tolerance; D007167:Immunotherapy; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008962:Models, Theoretical; D013601:T-Lymphocytes / Q000378:metabolism*; D014780:Viruses / Q000378:metabolism
D000941:Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins