Abstract
Antibodies specific for the hemagglutinin (HA) protein of influenza virus are critical for protective immunity to infection. Our studies show that CD4 T cells specific for epitopes derived from HA are the most effective in providing help for the HA-specific B cell responses to infection and vaccination. In this study, we asked whether HA epitopes recognized by CD4 T cells in the primary response to infection are equally distributed across the HA protein or if certain segments are enriched in CD4 T cell epitopes. Mice that collectively expressed eight alternative MHC (Major Histocompatibility Complex) class II molecules, that would each have different peptide binding specificities, were infected with an H1N1 influenza virus. CD4 T cell peptide epitope specificities were identified by cytokine EliSpots. These studies revealed that the HA-specific CD4 T cell epitopes cluster in two distinct regions of HA and that some segments of HA are completely devoid of CD4 T cell epitopes. When located on the HA structure, it appears that the regions that most poorly recruit CD4 T cells are sequestered within the interior of the HA trimer, perhaps inaccessible to the proteolytic machinery inside the endosomal compartments of antigen presenting cells.
Highlights
Influenza hemagglutinin (HA) is a major target of influenza vaccination because of the importance that this molecule plays in mediating binding and infection of influenza virus on host cells
Our studies show that in human vaccine responses to influenza, the serum antibody responses to HA are correlated with the elicitation of CD4 T cells specific for HA peptide epitopes and not those from other viral proteins contained in the vaccine, such as NP [11]
Our studies revealed that the epitopes selected for CD4 T cells in the primary response are localized to a limited number of “hot spots” within the HA protein and that there are corresponding “dead zones” that recruit very few CD4
Summary
Influenza hemagglutinin (HA) is a major target of influenza vaccination because of the importance that this molecule plays in mediating binding and infection of influenza virus on host cells. Because of this function, antibodies elicited by most influenza vaccine strategies have the potential to provide sterilizing immunity to influenza infection in the host (reviewed in [1,2,3,4,5,6,7]). Our studies show that in human vaccine responses to influenza, the serum antibody responses to HA are correlated with the elicitation of CD4 T cells specific for HA peptide epitopes and not those from other viral proteins contained in the vaccine, such as NP (nucleoprotein) [11]. The preceding studies suggest that, the human CD4 T cell repertoire is highly diverse with respect to reactivity to influenza viral proteins [13,14,15,16,17,18,19,20,21], understanding the specificity of CD4 T cells towards the HA protein is important
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