The Roles of Lymphoid Tissue Microenvironments in Guiding the Immune Response

Project Summary/Abstract Generation of adaptive immune responses to vaccines and infections necessitates highly coordinated crosstalk between cells of the innate and adaptive immune system. Using advanced imaging approaches, which we developed, we have recently established that lymph nodes are organized into discrete micro-environments (MEs) composed of different innate immune cell populations. In the past award cycle, we developed additional 3D quantitative imaging tools and described novel features of innate cell organization in lymph nodes. Moreover, we used these approaches to study how innate cell MEs change during distinct types of inflammation (Type-I vs. Type-II), and which MEs are associated with distinct types of T cell effector programming. We found that the generation of highly divergent innate MEs is involved in programing of Type-I vs. Type-II T cell responses. We also demonstrated that activation of T cells within distinct innate MEs leads to very rapid early heterogeneity in the developing adaptive immune response. These findings raise the central hypothesis of the current follow-up proposal, that lymphoid tissues are composed of a mosaic of innate MEs, which dynamically respond to specific inflammatory stimuli, and which are directly involved in the generation of distinct programs of T cell immunity. The Objectives and corresponding Specific Aims of this renewal proposal are: 1) to continue characterizing the cellular and molecular signaling events involved in the generation of innate cell MEs during Type-I inflammation; 2) to elucidate the roles of lymphatic drainage mediated antigen and agonist dispersal across lymphoid tissues in the establishment of diverse innate MEs and the generation of downstream adaptive response heterogeneity, and 3) to determine the impact of paracrine cell-cell signaling in driving the formation of Type-II MEs and Th2 cell differentiation (Aim 3). Our rationale is that a better understanding of how lymphoid tissue microanatomy impacts innate and adaptive cell crosstalk during distinct types of inflammation, will help reveal the underlying principles of immune response generation to vaccines and infections. A long-term goal of our studies is to use this information to develop novel approaches to manipulate immune responses directly in vivo. This would have major ramifications and clinical significance in improving human health.