Identification of a human HLA-E-restricted CD8⁺ T cell subset in volunteers immunized with Salmonella enterica serovar Typhi strain Ty21a typhoid vaccine

Our previous studies in volunteers immunized with Salmonella enterica serovar Typhi (S. Typhi) have suggested an important role for CD8⁺ T cells in host defense. In this study we describe a novel subset of neoclassical human HLA-E-restricted S. Typhi-specific CD8⁺ T cells derived from PBMC of Ty21a typhoid vaccinees. CD3⁺CD8⁺CD4 ^-CD56^- T cells effectively killed S. Typhi-infected targets regardless of whether they share classical HLA class I molecules with them, by a FAS-independent, granule-dependent mechanism, as evidenced by induction of granzyme B release and the blocking effects of concanamycin and strontium ions. The expression of HLA-E Ags, bat not CD1-a, -b, or -c, OB the membrane of S. Typhi-infected targets rendered them susceptible to lysis. Moreover, anti-HLA-E Abs partially blocked these responses. We also demonstrated that presentation of S. Typhi Ags via HLA-E could stimulate lFN-γ production. Increases in the net frequency of IFN-γ spot-forming cells were observed in the presence of targets coated with peptides that contain S. Typhi GroEL HLA-E binding motifs. These results demonstrate that HLA-E binds nonamer peptides derived from bacterial proteins and trigger CD8 ⁺-mediated lysis and IFN-γ production when exposed to infected targets, raising the possibility that this novel effector mechanism might contribute to host defense against intracellular bacterial infections.