Abstract
Adaptive immune responses protect against infection with dengue virus (DENV), yet cross-reactivity with distinct serotypes can precipitate life-threatening clinical disease. We found that clonotypes expressing the T cell antigen receptor (TCR) β-chain variable region 11 (TRBV11-2) were 'preferentially' activated and mobilized within immunodominant human-leukocyte-antigen-(HLA)-A∗11:01-restricted CD8 + T cell populations specific for variants of the nonstructural protein epitope NS3 133 that characterize the serotypes DENV1, DENV3 and DENV4. In contrast, the NS3 133 -DENV2-specific repertoire was largely devoid of such TCRs. Structural analysis of a representative TRBV11-2 + TCR demonstrated that cross-serotype reactivity was governed by unique interplay between the variable antigenic determinant and germline-encoded residues in the second β-chain complementarity-determining region (CDR2β). Extensive mutagenesis studies of three distinct TRBV11-2 + TCRs further confirmed that antigen recognition was dependent on key contacts between the serotype-defined peptide and discrete residues in the CDR2β loop. Collectively, these data reveal an innate-like mode of epitope recognition with potential implications for the outcome of sequential exposure to heterologous DENVs.
| Original language | English |
|---|---|
| Pages (from-to) | 1228-1237 |
| Number of pages | 10 |
| Journal | Nature Immunology |
| Volume | 18 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 18 Oct 2017 |
Keywords
- immunology
- infection
Cite this
}
Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8 + T cell response. / Culshaw, Abigail; Ladell, Kristin; Gras, Stephanie; McLaren, James E.; Miners, Kelly L.; Farenc, Carine; Van Den Heuvel, Heleen; Gostick, Emma; Dejnirattisai, Wanwisa; Wangteeraprasert, Apirath; Duangchinda, Thaneeya; Chotiyarnwong, Pojchong; Limpitikul, Wannee; Vasanawathana, Sirijitt; Malasit, Prida; Dong, Tao; Rossjohn, Jamie; Mongkolsapaya, Juthathip; Price, David A.; Screaton, Gavin R.
In: Nature Immunology, Vol. 18, No. 11, 18.10.2017, p. 1228-1237.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8 + T cell response
AU - Culshaw, Abigail
AU - Ladell, Kristin
AU - Gras, Stephanie
AU - McLaren, James E.
AU - Miners, Kelly L.
AU - Farenc, Carine
AU - Van Den Heuvel, Heleen
AU - Gostick, Emma
AU - Dejnirattisai, Wanwisa
AU - Wangteeraprasert, Apirath
AU - Duangchinda, Thaneeya
AU - Chotiyarnwong, Pojchong
AU - Limpitikul, Wannee
AU - Vasanawathana, Sirijitt
AU - Malasit, Prida
AU - Dong, Tao
AU - Rossjohn, Jamie
AU - Mongkolsapaya, Juthathip
AU - Price, David A.
AU - Screaton, Gavin R.
PY - 2017/10/18
Y1 - 2017/10/18
N2 - Adaptive immune responses protect against infection with dengue virus (DENV), yet cross-reactivity with distinct serotypes can precipitate life-threatening clinical disease. We found that clonotypes expressing the T cell antigen receptor (TCR) β-chain variable region 11 (TRBV11-2) were 'preferentially' activated and mobilized within immunodominant human-leukocyte-antigen-(HLA)-A∗11:01-restricted CD8 + T cell populations specific for variants of the nonstructural protein epitope NS3 133 that characterize the serotypes DENV1, DENV3 and DENV4. In contrast, the NS3 133 -DENV2-specific repertoire was largely devoid of such TCRs. Structural analysis of a representative TRBV11-2 + TCR demonstrated that cross-serotype reactivity was governed by unique interplay between the variable antigenic determinant and germline-encoded residues in the second β-chain complementarity-determining region (CDR2β). Extensive mutagenesis studies of three distinct TRBV11-2 + TCRs further confirmed that antigen recognition was dependent on key contacts between the serotype-defined peptide and discrete residues in the CDR2β loop. Collectively, these data reveal an innate-like mode of epitope recognition with potential implications for the outcome of sequential exposure to heterologous DENVs.
AB - Adaptive immune responses protect against infection with dengue virus (DENV), yet cross-reactivity with distinct serotypes can precipitate life-threatening clinical disease. We found that clonotypes expressing the T cell antigen receptor (TCR) β-chain variable region 11 (TRBV11-2) were 'preferentially' activated and mobilized within immunodominant human-leukocyte-antigen-(HLA)-A∗11:01-restricted CD8 + T cell populations specific for variants of the nonstructural protein epitope NS3 133 that characterize the serotypes DENV1, DENV3 and DENV4. In contrast, the NS3 133 -DENV2-specific repertoire was largely devoid of such TCRs. Structural analysis of a representative TRBV11-2 + TCR demonstrated that cross-serotype reactivity was governed by unique interplay between the variable antigenic determinant and germline-encoded residues in the second β-chain complementarity-determining region (CDR2β). Extensive mutagenesis studies of three distinct TRBV11-2 + TCRs further confirmed that antigen recognition was dependent on key contacts between the serotype-defined peptide and discrete residues in the CDR2β loop. Collectively, these data reveal an innate-like mode of epitope recognition with potential implications for the outcome of sequential exposure to heterologous DENVs.
KW - immunology
KW - infection
UR - http://www.scopus.com/inward/record.url?scp=85031784242&partnerID=8YFLogxK
U2 - 10.1038/ni.3850
DO - 10.1038/ni.3850
M3 - Article
VL - 18
SP - 1228
EP - 1237
JO - Nature Immunology
JF - Nature Immunology
SN - 1529-2908
IS - 11
ER -