Deciphering and predicting CD4+ T cell immunodominance of influenza virus hemagglutinin #MMPMID32644114
Cassotta A; Paparoditis P; Geiger R; Mettu RR; Landry SJ; Donati A; Benevento M; Foglierini M; Lewis DJM; Lanzavecchia A; Sallusto F
J Exp Med 2020[Oct]; 217 (10): ? PMID32644114show ga
The importance of CD4+ T helper (Th) cells is well appreciated in view of their essential role in the elicitation of antibody and cytotoxic T cell responses. However, the mechanisms that determine the selection of immunodominant epitopes within complex protein antigens remain elusive. Here, we used ex vivo stimulation of memory T cells and screening of naive and memory T cell libraries, combined with T cell cloning and TCR sequencing, to dissect the human naive and memory CD4+ T cell repertoire against the influenza pandemic H1 hemagglutinin (H1-HA). We found that naive CD4+ T cells have a broad repertoire, being able to recognize naturally processed as well as cryptic peptides spanning the whole H1-HA sequence. In contrast, memory Th cells were primarily directed against just a few immunodominant peptides that were readily detected by mass spectrometry-based MHC-II peptidomics and predicted by structural accessibility analysis. Collectively, these findings reveal the presence of a broad repertoire of naive T cells specific for cryptic H1-HA peptides and demonstrate that antigen processing represents a major constraint determining immunodominance.
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J+Exp+Med 2020 ; 217 (10): ?
