Major TCR repertoire perturbation by immunodominant HLA-B*44:03-restricted CMV-specific T cells
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 wh...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Frontiers Media
2018
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| _version_ | 1826282223868837888 |
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| author | Attaf, M Malik, A Severinsen, M Roider, J Ogongo, P Buus, S Ndung'U, T Leslie, A Kløverpris, H Matthews, P Sewell, A Goulder, P |
| author_facet | Attaf, M Malik, A Severinsen, M Roider, J Ogongo, P Buus, S Ndung'U, T Leslie, A Kløverpris, H Matthews, P Sewell, A Goulder, P |
| author_sort | Attaf, M |
| collection | OXFORD |
| description | 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*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*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*44:03 individuals. |
| first_indexed | 2024-03-07T00:40:36Z |
| format | Journal article |
| id | oxford-uuid:82e4263a-0f0d-4563-97fe-293972a7d6e0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:40:36Z |
| publishDate | 2018 |
| publisher | Frontiers Media |
| record_format | dspace |
| spelling | oxford-uuid:82e4263a-0f0d-4563-97fe-293972a7d6e02022-03-26T21:40:39ZMajor TCR repertoire perturbation by immunodominant HLA-B*44:03-restricted CMV-specific T cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:82e4263a-0f0d-4563-97fe-293972a7d6e0EnglishSymplectic Elements at OxfordFrontiers Media2018Attaf, MMalik, ASeverinsen, MRoider, JOgongo, PBuus, SNdung'U, TLeslie, AKløverpris, HMatthews, PSewell, AGoulder, PLack 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*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*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*44:03 individuals. |
| spellingShingle | Attaf, M Malik, A Severinsen, M Roider, J Ogongo, P Buus, S Ndung'U, T Leslie, A Kløverpris, H Matthews, P Sewell, A Goulder, P Major TCR repertoire perturbation by immunodominant HLA-B*44:03-restricted CMV-specific T cells |
| title | Major TCR repertoire perturbation by immunodominant HLA-B*44:03-restricted CMV-specific T cells |
| title_full | Major TCR repertoire perturbation by immunodominant HLA-B*44:03-restricted CMV-specific T cells |
| title_fullStr | Major TCR repertoire perturbation by immunodominant HLA-B*44:03-restricted CMV-specific T cells |
| title_full_unstemmed | Major TCR repertoire perturbation by immunodominant HLA-B*44:03-restricted CMV-specific T cells |
| title_short | Major TCR repertoire perturbation by immunodominant HLA-B*44:03-restricted CMV-specific T cells |
| title_sort | major tcr repertoire perturbation by immunodominant hla b 44 03 restricted cmv specific t cells |
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