Computational Methods for Predicting Key Interactions in T Cell-Mediated Adaptive Immunity.

The adaptive immune system recognizes pathogen- and cancer-specific features and is endowed with memory, enabling it to respond quickly and efficiently to repeated encounters with the same antigens. T cells play a central role in the adaptive immune system by directly targeting intracellular pathogens and helping to activate B cells to secrete antibodies. Several fundamental protein interactions-including those between major histocompatibility complex (MHC) proteins and antigen-derived peptides as well as between T cell receptors and peptide-MHC complexes-underlie the ability of T cells to recognize antigens with great precision. Computational approaches to predict these interactions are increasingly being used for medically relevant applications, including vaccine design and prediction of patient response to cancer immunotherapies. We provide computational researchers with an accessible introduction to the adaptive immune system, review computational approaches to predict the key protein interactions underlying T cell-mediated adaptive immunity, and highlight remaining challenges.

Chronic Glucose Exposure Systematically Shifts the Oscillatory Threshold of Mouse Islets: Experimental Evidence for an Early Intrinsic Mechanism of Compensation for Hyperglycemia.

Mouse islets exhibit glucose-dependent oscillations in electrical activity, intracellular Ca(2+) and insulin secretion. We developed a mathematical model in which a left shift in glucose threshold helps compensate for insulin resistance. To test this experimentally, we exposed isolated mouse islets to varying glucose concentrations overnight and monitored their glucose sensitivity the next day by measuring intracellular Ca(2+), electrical activity, and insulin secretion. Glucose sensitivity of all oscillation modes was increased when overnight glucose was greater than 2.8mM. To determine whether threshold shifts were a direct effect of glucose or involved secreted insulin, the KATP opener diazoxide (Dz) was coapplied with glucose to inhibit insulin secretion. The addition of Dz or the insulin receptor antagonist s961 increased islet glucose sensitivity, whereas the KATP blocker tolbutamide tended to reduce it. This suggests insulin and glucose have opposing actions on the islet glucose threshold. To test the hypothesis that the threshold shifts were due to changes in plasma membrane KATP channels, we measured cell KATP conductance, which was confirmed to be reduced by high glucose pretreatment and further reduced by Dz. Finally, treatment of INS-1 cells with glucose and Dz overnight reduced high affinity sulfonylurea receptor (SUR1) trafficking to the plasma membrane vs glucose alone, consistent with insulin increasing KATP conductance by altering channel number. The results support a role for metabolically regulated KATP channels in the maintenance of glucose homeostasis.