Prevention of Cytotoxic T Cell Escape Using a Heteroclitic Subdominant Viral T Cell Determinant

High affinity antigen-specific T cells play a critical role during protective immune responses. Epitope enhancement can elicit more potent T cell responses and can subsequently lead to a stronger memory pool; however, the molecular basis of such enhancement is unclear. We used the consensus peptide-binding motif for the Major Histocompatibility Complex molecule H-2Kb to design a heteroclitic version of the mouse hepatitis virus-specific subdominant S598 determinant. We demonstrate that a single amino acid substitution at a secondary anchor residue (Q to Y at position 3) increased the stability of the engineered determinant in complex with H-2Kb. The structural basis for this enhanced stability was associated with local alterations in the pMHC conformation as a result of the Q to Y substitution. Recombinant viruses encoding this engineered determinant primed CTL responses that also reacted to the wildtype epitope with significantly higher functional avidity, and protected against selection of virus mutated at a second CTL determinant and consequent disease progression in persistently infected mice. Collectively, our findings provide a basis for the enhanced immunogenicity of an engineered determinant that will serve as a template for guiding the development of heteroclitic T cell determinants with applications in prevention of CTL escape in chronic viral infections as well as in tumor immunity

Innovative partnerships to advance public health training in community-based academic residency programs

Joan C Lo,1–3 Thomas E Baudendistel,2,3 Abhay Dandekar,3,4 Phuoc V Le,5 Stanton Siu,2,3 Bruce Blumberg6 1Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA; 2Department of Medicine, Kaiser Permanente Oakland Medical Center, Oakland, CA, USA; 3Graduate Medical Education, Kaiser Permanente East Bay, Oakland, CA, USA; 4Department of Pediatrics, Kaiser Permanente Oakland Medical Center, Oakland, CA, USA; 5School of Public Health, University of California Berkeley, Berkeley, CA, USA; 6Graduate Medical Education, Kaiser Permanente Northern California, Oakland, CA, USA Abstract: Collaborative partnerships between community-based academic residency ­training programs and schools of public health, represent an innovative approach to training future physician leaders in population management and public health. In Kaiser Permanente Northern California, development of residency-Masters in Public Health (MPH) tracks in the Internal Medicine Residency and the Pediatrics Residency programs, with MPH graduate studies completed at the University of California Berkeley School of Public Health, enables physicians to integrate clinical training with formal education in epidemiology, biostatistics, health policy, and disease prevention. These residency-MPH programs draw on more than 50 years of clinical education, public health training, and health services research – creating an environment that sparks inquiry and added value by developing skills in patient-centered care through the lens of population-based outcomes. Keywords: graduate medical education, public health, master’s degree, internal medicine, pediatrics, residency trainin