Publication date: Jan 28, 2025

Although antibody escape is observed in emerging severe acute respiratory syndrome coronavirus 2 variants, T cell escape, especially after the global circulation of BA. 2.86/JN. 1, is unexplored. Here we demonstrate that T cell evasion exists in epitope hotspots spanning BA. 2.86/JN. 1 mutations. The newly emerging Q229K at this conserved nucleocapsid protein site impairs HLA-A2 epitope hotspot recognition. The association between HLA-A24 convalescents and T cell immune escape points to the spike (S) protein epitope SNYNYLYRLF, with multiple mutations from Delta to JN. 1, including L452Q, L452R, F456L, N450D and L452W, and N450D, L452W and L455S. A cliff drop of immune responses was observed for SNYNYRYRLF (Delta/BA. 5.2) and SNYDYWYRSF (JN. 1), but with immune preservation of SNYDYWYRLF (BA. 2.86). Structural analyses showed that hydrophobicity exposure determines the pronounced escape of L452R and L455S mutants, which was further confirmed by T cell receptor binding. This study highlights the characteristics and molecular mechanisms of the T cell immune escape for JN. 1 and provides new insights into understanding the dominant circulation of variants, from the viewpoint of cytotoxic T cell evasion.

Semantics

Original Article