The immune response of BALB/c mice to influenza hemagglutinin: commonality of the B cell and T cell repertoires and their relevance to antigenic drift

Abstract

An extensive analysis of the class II (I-Ad)-restricted T cell repertoire for influenza hemagglutinin (HA) of the H3 subtype, elicited by natural infection, has shown that majority of CD4+ memory T cell clones focus on antibody-binding regions of HA, sites B and E, and are sensitive to the residue substitutions that have occurred in these regions during antigenic drift. The proliferative responses of CD4+ clones to synthetic peptides have identified T cell epitopes within site B, HA1 177-199 and HA1 182-199, and site E. HA1 56-76. The recognition specificity of T cell clones for antibody-selected mutant viruses, with single amino acid substitutions within these recognition sites identified residues 63, 189, 193 and 198 as being important for T cell recognition and thus established that BALB/c, CD4+ T cell clones were sensitive to the same substitutions known to abrogate BALB/c antibody recognition of the native HA. Our findings indicate extensive commonality of the B cell and T cell repertoires for HA, which may be relevant to an understanding of the immune pressures for antigenic drift, and, moreover, suggest that the antigen-specific B memory cell may be instrumental in selection of the peripheral T cell repertoire.

Clustering of Th Cell Epitopes on Exposed Regions of HIV Envelope Despite Defects in Antibody Activity

“…The clustering of Th epitopes on outer protein surfaces has been described in other viral systems and has been hypothesized to be a consequence of Ab-mediated Ag processing (18,38). As shown in Fig.…”

“…2) Abs bind the outer surfaces of proteins and protect associated fragments from degradation. Select peptides are thus preserved for downstream Ag processing (18,19,22,23).…”

Focused antibody response to influenza linked to antigenic drift

“…The mechanism by which this focusing of the antibody response occurs is not clear from these data, but three possibilities include (a) a limited response in the first exposure to a new virus (13), (b) selection of cross-reacting B cells from the available repertoire induced by earlier exposure to related influenza viruses (15, 16, 25, 34-37, 41, 44, 47, 56, 57), or (c) the selection and expansion of B cells making antibodies that influence antigen processing and presentation to T cells in such a way that optimizes T cell help, "T-B reciprocity" (33,(58)(59)(60)(61)(62). These mechanisms are not mutually exclusive and could act together.…”

Reduction of the inhibitory antibody response to human factor VIII in hemophilia A mice by mutagenesis of the A2 domain B-cell epitope

“…50 However, occasionally B-and T-cell epitopes do overlap. 51 Additionally, in some cases, antibody binding to antigen can enhance the presentation of a T-cell determinant while simultaneously suppressing the presentation of another T-cell determinant within the same antibody footprint. 52 Overlap of B-and T-cell epitopes was identified in a patient with mild hemophilia A that was produced by an R2150H missense mutation in the fVIII C1 domain.…”