Human influenza reactivity to conserved influenza hemagglutinin and its relation to age and repeat vaccination

Abstract

The first exposures to influenza have been shown to bias the immune system towards a certain strain which is then boosted by subsequent infection and vaccination throughout life. The impact of repeated stimulation of hemagglutinin (HA) epitopes of the CD4 T cell repertoire is unknown. We are interested in the CD4 T cells specific to conserved regions of HA as the conserved stalk region is a target for new vaccine designs and antibodies to HA are a correlate of protection from infection. We are also interested in how CD4 T cell phenotypes after repeated antigen exposure from conserved HA epitopes could change the CD4 T cell repertoire. In order to probe these questions, we analyzed PBMCs collected from healthy human donors using cytokine ELISpots and flow cytometry. We created overlapping peptide pools containing conserved or unique regions of HA, to compare differences in cytokine secretion, abundance, and phenotypes of CD4 T cells elicited to different regions of HA. Our hypothesis is that CD4 T cells specific to repeatedly stimulated epitopes will have a higher frequency and different phenotypes compared to unique epitopes. We have found that there is a robust circulating CD4 T cell response to influenza antigens. The reactivity to conserved regions of HA varies between individuals as well as between strains of influenza in healthy human donors and in some donors, there are CD4 T cells that are biased towards conserved regions of HA. Those CD4 T cells to conserved regions of the stalk could be recalled after vaccination with stalk-based vaccine strategies. We plan to further examine the phenotypes of those CD4 T cells and to determine if decade of birth and vaccination history will impact the abundance of CD4 T cells to conserved HA regions.