Temporal protein expression pattern in intracellular signalling cascade during T-cell activation: A computational study

Abstract

Various T-cell co-receptor molecules and calcium channel CRAC play a pivotal role in the maintenance of cell's functional responses by regulating the production of effector molecules (mostly cytokines) that aids in immune clearance and also maintaining the cell in a functionally active state. Any defect in these co-receptor signalling pathways may lead to an altered expression pattern of the effector molecules. To study the propagation of such defects with time and their effect on the intracellular protein expression patterns, a comprehensive and largest pathway map of T-cell activation network is reconstructed manually. The entire pathway reactions are then translated using logical equations and simulated using the published time series microarray expression data as inputs. After validating the model, the effect of in silico knock down of co-receptor molecules on the expression patterns of their downstream proteins is studied and simultaneously the changes in the phenotypic behaviours of the T-cell population are predicted, which shows significant variations among the proteins expression and the signalling routes through which the response is propagated in the cytoplasm. This integrative computational approach serves as a valuable technique to study the changes in protein expression patterns and helps to predict variations in the cellular behaviour.

Identification of Th1/Th2 regulatory switch to promote healing response during leishmaniasis: a computational approach

“…LPG_L, GP63_L, LFAA_L, and EF1_ALPHA_L, are known to be present in almost all the Leishmania species so as to create a generalized Leishmania infection model (LFAA_L is a hypothetical molecule which we considered in our model to show the activation of ASMASE for the production of CERAMIDE [ 41 ]; it is abbreviated for Leishmania factor activating ASMASE). With certain modifications (required to build the juxtacrine and paracrine interactions between the cells), the T cell pathway reported in our previous work was used to understand the T cell-APC cross-talks and to monitor the immunological response generated during Leishmania infection [ 31 ]. The pathway figure was drawn using Cell Designer software (version 4.3) [ 42 ].…”

“…It is to be mentioned here that since the expression of the output proteins is the best reflection of functioning of the entire signaling cascade, the validation of these previously mentioned ten output molecules is assumed to be sufficient to demonstrate the authenticity of the entire model. The T cell model was also validated in a similar way, i.e., by comparing the time-course expression profile of the output protein molecules as obtained in the synchronous simulation with the experimental data [ 31 ].…”

“…Large scale, intracellular T cell signaling network is also analyzed by using this modeling technique and eventually various structural and functional properties of this network under normal and disease conditions are studied successfully [ 29 , 30 ]. A logic-based modeling technique is also applied to analyze the temporal expression patterns of the genes/proteins of T cell, which are strongly influenced by the intra-cellular T cell signal transduction cascade in presence or absence of infection [ 31 ].…”