Development of thymocytes involves two distinct outcomes resulting from superficially similar events. Recognition by thymocytes of major histocompatibility complex (MHC) proteins plus peptides leads to their rescue from apoptosis (positive selection), and recognition of antigenic peptide induces cell death (negative selection). Antigen analogues, and sometimes low concentrations of antigenic peptide, induce positive selection; such analogues are often antagonists of mature T-cell clones. Various models seek to explain how recognition of different peptide/MHC complexes leads to such different outcomes: quantitative models relate response to the affinity, avidity or kinetics of T-cell-antigen receptor (TCR) binding, whereas qualitative models require conformational or spatial changes in the TCR or associated molecules to modulate signal transduction. We have used surface plasmon resonance to measure the kinetics of TCR interactions with positively and negatively selecting ligands to distinguish between these models, and find that affinity correlates to the outcome of selection. A 'window' of affinity resulting in positive selection extends over a 1-log range starting threefold below the affinity for negative selection.
Non-small cell lung cancers (NSCLCs) bearing mutations in the tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) often exhibit dramatic sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Ionizing radiation (IR) is frequently used in the treatment of NSCLC, but little is known how lung tumor-acquired EGFR mutations affect responses to IR. Because this is of great clinical importance, we investigated and found that clonogenic survival of mutant EGFR NSCLCs in response to IR was reduced 500-to 1,000-fold compared with wild-type (WT) EGFR NSCLCs. Exogenous expression of either the L858R point mutant or the #E746-E750 deletion mutant form of EGFR in immortalized human bronchial epithelial cells, p53 WT NSCLC (A549), or p53-null NSCLC (NCI-H1299) resulted in dramatically increased sensitivity to IR. We show that the majority of mutant EGFR NSCLCs, including those that contain the secondary gefitinib resistance T790M mutation, exhibit characteristics consistent with a radiosensitive phenotype, which include delayed DNA repair kinetics, defective IR-induced arrest in DNA synthesis or mitosis, and pronounced increases in apoptosis or micronuclei. Thus, understanding how activating mutations in the TKD domain of EGFR contribute to radiosensitivity should provide new insight into effective treatment of NSCLC with radiotherapy and perhaps avoid emergence of single agent drug resistance.
The dynamics of the relationship between the immune system and latent viruses are highly complex. Latent viruses not only avoid elimination by the host's primary immune response, they also remain with the host for life in the presence of strong acquired immunity, often exhibiting periodic reactivation and recurrence from the latent state. The continual battle between reemergent infectious virus and immunological memory cells provides an essential virus-host regulatory loop in latency. In this review, we speculate on the critical importance of immune interference mechanisms by viruses contributing to the regulatory loop in viral homeostasis of latency. Central to the notion of viral homeostasis, we further invoke the concept of threshold limits in naive and memory states of immunity to account for the failure of the host to completely eradicate these intracellular parasites.
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