Abstract
Abstract The foundation of successful vaccines lies in the ability to prime the immune system to target a specific pathogen. The interaction between follicular helper T cells (Tfh) and B cells within germinal centers is necessary for the production of class-switched, affinity-matured antibodies. However, the size, diversity, and specificity of the T cell receptor (TCR) repertoire of the Tfh during an immune response remains unknown. We identified a subset of circulating Tfh (cTfh) coexpressing ICOS and CD38 that expresses markers of recent activation, such as the proliferation marker Ki67 and the transcription factor Helios. This activated cTfh subset increases following influenza vaccination. To begin to interrogate how the TCR repertoire changes in human cTfh cells responding to a vaccine, we performed T-cell receptor beta chain sequencing on cTfh from individuals before and after influenza vaccination. Although the ICOS−CD38− cTfh maintained a stable TCR repertoire pre- and 7 days post vaccination, the ICOS+CD38+ cTfh exhibited increased clonality indicative of antigen-driven activation and expansion. Using HLA class II HA306- and HA40-specific tetramer staining on peripheral blood from HLA-DR0401 individuals, we then further assessed the specificity of the responding cTfh at day 7 after vaccination. We found many tetramer-positive cells that expressed ICOS and CD38 in the cTfh subset, confirming that the ICOS+CD38+ response after vaccination contains influenza-specific cells. Ultimately, rational vaccine design will depend on better understanding of the clonotypic response elicited in response to various pathogens and their relevance to the overall immune response.
Published Version
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