Image_3_Major TCR Repertoire Perturbation by Immunodominant HLA-B*44:03-Restricted CMV-Specific T Cells.TIFF Meriem Attaf Amna Malik Mai C. Severinsen Julia Roider Paul Ogongo Søren Buus Thumbi Ndung'u Alasdair Leslie Henrik N. Kløverpris Philippa C. Matthews Andrew K. Sewell Philip Goulder 10.3389/fimmu.2018.02539.s003 https://frontiersin.figshare.com/articles/figure/Image_3_Major_TCR_Repertoire_Perturbation_by_Immunodominant_HLA-B_44_03-Restricted_CMV-Specific_T_Cells_TIFF/7336967 <p>Lack of disease during chronic human cytomegalovirus (CMV) infection depends on the maintenance of a high-frequency CMV-specific T cell response. The composition of the T cell receptor (TCR) repertoire underlying this response remains poorly characterised, especially within African populations in which CMV is endemic from infancy. Here we focus on the immunodominant CD8+ T cell response to the immediate-early 2 (IE-2)-derived epitope NEGVKAAW (NW8) restricted by HLA-B<sup>*</sup>44:03, a highly prevalent response in African populations, which in some subjects represents >10% of the circulating CD8+ T cells. Using pMHC multimer staining and sorting of NW8-specific T cells, the TCR repertoire raised against NW8 was characterised here using high-throughput sequencing in 20 HLA-B<sup>*</sup>44:03 subjects. We found that the CD8+ T cell repertoire raised in response to NW8 was highly skewed and featured preferential use of a restricted set of V and J gene segments. Furthermore, as often seen in immunity against ancient viruses like CMV and Epstein-Barr virus (EBV), the response was strongly dominated by identical TCR sequences shared by multiple individuals, or “public” TCRs. Finally, we describe a pair “superdominant” TCR clonotypes, which were germline or nearly germline-encoded and produced at remarkably high frequencies in certain individuals, with a single CMV-specific clonotype representing up to 17% of all CD8+ T cells. Given the magnitude of the NW8 response, we propose that this major skewing of CMV-specific immunity leads to massive perturbations in the overall TCR repertoire in HLA-B<sup>*</sup>44:03 individuals.</p> 2018-11-14 04:15:53 T cell T cell receptor cytomegalovirus HLA-B*44:03 repertoire sequencing