Adaptive threshold-stochastic resonance (AT-SR) in MHC clusters on the cell surface.

Highly conserved 2D receptor clusters (membrane rafts) of immunological signaling molecules with MHCI and MHCII antigens as their cores have been observed in the past on the surface of T- and B-cell lines of lymphoid origin, as well as on cells from patients with colon tumor and Crohn's disease. Conservativity is related to the ever presence of MHCI molecules. Although they are suspected to play a role in maintaining these clusters and facilitating transmembrane signaling, their exact role has been left largely enigmatic. Here we are suggesting stochastic resonance (SR), or "noise-assisted signal detection", as a general organizing principle for transmembrane signaling events evoked by processes like immune recognition and cytokine binding taking place in these clusters. In the conceptual framework of SR, in immune recognition as a prototype of transmembrane signaling, the sea of self-peptide-MHC complexes around a nonself-peptide presenting MHC is conceived as a source of quickly fluctuating unspecific signal ("athermal noise") serving the extra energy for amplifying the weak sub-threshold specific signal of the nonself-peptide presenting MHC. This same noise is also utilized for a readjustment of the threshold - and also the sensitivity and specificity - of detection by a closed loop feedback control of the TcR-CD8 (CD4) proximity on the detecting T-cell. The weak sub threshold specific signal of nonself-peptide presenting MHC is amplified by the superposing unspecific signals of the neighboring self peptide-MHC complexes towards the T-cell receptor as the detector. Because in a successful detection event both self- and nonself-peptides are detected simultaneously, the principle of coincidence (or lock-in) detection is also realized. The ever presence of MHC islands gets a natural explanation as a source of extra power - in a form of "athermal noise" - needed for coincidence detection and frequency encoding the evoked downstream signals. The effect is quite general, because the actual type of molecules surrounding a chief signaling molecule - like nonself-peptide holding MHC, interleukin-2 and -15 cytokine receptors (IL-2R/15R) - as the fluctuating interaction energy sources is immaterial. The model applies also for other types of signaling, such as those evoked by cytokine binding. The phenomenon of SR can also be interpreted as sampling of a low frequency, specific signal with a high frequency unspecific signal, the "noise". Recipes for identifying other forms of SR in membrane clusters with biophysical tools are recommended.