Spatial Clustering of Receptors and Signaling Molecules Regulates NK Cell Response to Peptide Repertoire Changes

Natural Killer (NK) cell activation requires integration of inhibitory and activating signaling. Inhibitory signals are determined by members of the killer cell immunoglobulin-like receptor (KIR) family, which have major histocompatibility complex (MHC) class I ligands. Loss of this inhibitory signal leads to NK cell activation. Thus, down-regulation of MHC I during viral infection or cancer induces NK cell activation. However, NK cell activation in the presence of MHC-I has been demonstrated for HLA-C*0102 through changes in its peptide content: “peptide antagonism.” Here we identify an antagonist peptide for HLA-C*0304 suggesting that peptide antagonism is a generalizable phenomenon and, using a combination of mathematical modeling, confocal imaging, and immune-assays, we quantitatively determine mechanisms that underlie peptide antagonism in inhibitory KIR2DL2/3 signaling. These data provide a mechanism for NK cell activation based on a reduction of inhibitory signaling in the presence of preserved levels of MHC class I

Positive Feedback Regulation Results in Spatial Clustering and Fast Spreading of Active Signaling Molecules on a Cell Membrane

Positive feedback regulation is ubiquitous in cell signaling networks, often leading to binary outcomes in response to graded stimuli. However, the role of such feedbacks in clustering, and in spatial spreading of activated molecules, has come to be appreciated only recently. We focus on the latter, using a simple model developed in the context of Ras activation with competing negative and positive feedback mechanisms. We find that positive feedback, in the presence of slow diffusion, results in clustering of activated molecules on the plasma membrane, and rapid spatial spreading as the front of the cluster propagates with a constant velocity (dependent on the feedback strength). The advancing fronts of the clusters of the activated species are rough, with scaling consistent with the Kardar-Parisi-Zhang (KPZ) equation in one dimension. Our minimal model is general enough to describe signal transduction in a wide variety of biological networks where activity in the membrane-proximal region is subject to feedback regulation.Comment: 37 pages, 8 figures. Journal of Chemical Physics (in press

Maximum Entropy estimation of probability distribution of variables in higher dimensions from lower dimensional data

A common statistical situation concerns inferring an unknown distribution Q(x) from a known distribution P(y), where X (dimension n), and Y (dimension m) have a known functional relationship. Most commonly, n<m, and the task is relatively straightforward. For example, if Y1 and Y2 are independent random variables, each uniform on [0, 1], one can determine the distribution of X = Y1 + Y2; here m=2 and n=1. However, biological and physical situations can arise where n>m. In general, in the absence of additional information, there is no unique solution to Q in those cases. Nevertheless, one may still want to draw some inferences about Q. To this end, we propose a novel maximum entropy (MaxEnt) approach that estimates Q(x) based only on the available data, namely, P(y). The method has the additional advantage that one does not need to explicitly calculate the Lagrange multipliers. In this paper we develop the approach, for both discrete and continuous probability distributions, and demonstrate its validity. We give an intuitive justification as well, and we illustrate with examples.Comment: in revie

Dynamics of Ordering of Isotropic Magnets

We study the dynamics of ordering of the nonconserved and conserved Heisenberg magnet. The dynamics consists of two parts - an irreversible dissipation into a heat bath and a reversible precession induced by a torque due to the local molecular field. For quenches both to T=0 and T=T_c, we show that the torque is irrelevant when the dynamics is nonconserved but relevant when the dynamics is conserved and is governed by a new nontrivial fixed point.Comment: 7 pages, 5 eps figures. To appear in Physica A as a part of the proceedings of the StatPhys - Calcutta III, January 1999, Calcutta, India. Largely a combination of Phys. Rev. E, {\bf 57}, (1998),5069 and cond-mat/9903041, together with a detailed discussion on multiscalin