Protein vaccination is an effective public health initiative with demonstrable utility in the prevention of infectious. An effective immune response to protein antigen relies on the helper T cell regulated development of high-affinity B cell memory and its consolidation after the vaccine boost. The cognate control of B cell immunity requires a spectrum of specialized effector Th cell functions that are temporally and spatially separated in vivo, the subsequent development of antigen-specific Th cell memory and the regulated re-activation of B cell memory responses. Clonal selection underpins the evolution of adaptive immunity in the Th cell and B cell compartment. Our recent studies indicate a unique set of rules for antigen- specific Th cells that control clonal recruitment and cellular expansion in vivo. Sequential selection events based on TCR-pMHCII affinity thresholds shape TCR diversity and regulate clonal dominance in the Th cell compartment. We hypothesize that the differential strength of TCR recognition is also a major determinant in priming effector Th cell function, shaping the memory Th cell compartment and re-shaping the memory response to antigen recall. We will determine the how TCR recognition controls evolution of effector cell evolution and function over the primary response to protein vaccination (SA1). We will then examine the impact of TCR recognition on the development of antigen-specific Th cell memory and the capacity of memory Th cells to respond to antigen recall. Over the course of these studies, we will provide fundamental new insights into the mechanisms controlling adaptive immunity and help to define the best means to obtain long-lasting high affinity B cell immunity to protein antigens. Protein vaccination is an important and effective preventative public health initiative. Vaccinating against sub-components of pathogens is a safe approach to vaccine design. However, we still don't fully understand how the immune system responds to these challenges and how the system develops a memory for what its seen. Our work seeks to understand how the system works in order to design better vaccine that promote stronger, longer lasting protective immune memory.
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