While many strides have been made in the study of human immune responses, numerous knowledge gaps still remain. Many infections and immune-mediated diseases are localized to specific tissues, or organs but little is known about tissue/organ-specific immunity. A major overall goal of this CCHI program to this end is to understand memory CD8 T cells differentiation in the blood, tissues and organs. We have added Dr. Donna Farber to our CHHI-EVC team this cycle. She has established a unique human tissue resource enabling acquisition of blood and various tissues from deceased organ donors, we will therefore analyze virus-specific memory CD8 T cells in various tissues of deceased organ donors and address questions regarding the anatomic distribution and the epigenetic, transcriptional and phenotypic profile of virus-specific CD8 T cells elicited by live- attenuated virus vaccines and with minimal risk of antigenic re-exposure. The second major goal of this program is to elucidate the molecular mechanisms of “trained immunity” after YFV vaccination and viral infection to and harness this knowledge for future development of new classes of vaccines and immunotherapies. We will address the following questions. To what extent is so called “innate memory” caused by the effects of an ongoing adaptive immune response (for example, via paracrine signaling), versus a cell intrinsic property of innate cells, similar to the classic phenomenon of immune memory exhibited by memory T or B cells? Is there an enhanced response of DCs and monocytes, (similar to a memory response in the adaptive immune system), during secondary vaccination or infection? If so, what are the cellular and molecular mechanisms involved? Finally, the third overall goal is to identify signaling and transcription factor (TF) networks associated with T memory cell differentiation and survival and quantify how these networks change with age. This will be achieved in the following projects: Project 1: Immune memory (Ahmed, Hellerstein, Farber); Project 2: Innate immunity (Pulendran, Hellerstein), and Project 3: Immune senescence (Goronzy, Greenleaf). Supported by the following Core A: Adminstration (Ahmed); Core B: Single cell and integrative genomics (Bosinger, Greenleaf); Core C: Clinical and biostatistical (Edupuganti, Kulkanya, Yu).

The studies proposed in this CCHI application on human CD8 T cell memory in blood and tissues, on mechanisms of trained innate immunity, and on molecular mechanisms of T cell aging will provide a framework for the rational design of vaccines that elicit long-term protective immunity.