Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8⁺ T cell response

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 NS3₁₃₃ that characterize the serotypes DENV1, DENV3 and DENV4. In contrast, the NS3₁₃₃-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.