CD8 + regulatory T cells limit immunopathology but impair viral clearance in Hantaan virus infection

In hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus (HTNV), virus-specific CD8 + T cells mediate both viral clearance and immunopathology. Here, we characterized a CD8 + regulatory T cell (Treg) subset restricted by HLA-E (and its murine ortholog Qa-1) in HFRS patients and in a murine HTNV infection model. CD8 + Tregs (CD122 + Eomes + CD49d lo KIR + ), a subset substantially enriched for HLA-E-restricted T cells, were significantly reduced in peripheral blood of HFRS patients and displayed a terminally differentiated profile with elevated expression of KLRG-1, NKG2A, CTLA-4, and Fas-L, correlating with disease severity. Two HTNV glycoprotein-derived nonapeptides that bound Qa-1 were identified. Following immunization with the identified HTNV peptides and subsequent HTNV challenge, wild-type (WT) mice showed attenuated renal immunopathology, whereas D227K knock-in mice (with disrupted Qa-1-CD8/TCR interaction) showed enhanced viral clearance in the spleen and kidney but exacerbated renal immunopathology. Mechanistically, Qa-1-restricted CD8 + Tregs from WT mice suppressed effector CD8 + T cell proliferation in a peptide-specific, CD8/TCR-dependent manner via enhanced TGF-β secretion. Strikingly, D227K mutation dichotomously reshaped Treg phenotype: bulk polyclonal CD8 + Tregs displayed compensatory upregulation of inhibitory receptors (NKG2A, CTLA-4, PD-1) and TGF-β, whereas epitope-specific CD8 + Tregs showed impaired antigen-specific suppressive function and attenuated TGF-β production. Collectively, these findings indicate that HLA-E/Qa-1-restricted CD8 + Tregs can restrain immunopathology during HTNV infection, potentially at the cost of delayed viral elimination. Modulation of this axis may provide insights for therapeutic strategies in HFRS and related viral hemorrhagic fevers.