SignificanceMucosa-associated invariant T (MAIT) cells are unconventional innate-like T cells recognizing microbial riboflavin metabolites presented by the monomorphic MR1 molecule. Here, we show that the CD8+CD4− and CD8−CD4− subpopulations of human MAIT cells represent transcriptionally and phenotypically discrete subsets with distinct functional profiles. Furthermore, T cell receptor repertoire analysis, as well as MAIT cell data based on human fetal tissues, umbilical cord blood, and culture systems indicate that the CD8−CD4− subset may derive from the main CD8+CD4− MAIT cell pool. Thus, MAIT cells, a major antimicrobial effector T cell population in humans, segregate into two functionally distinct but developmentally related subsets separated by the expression of CD8. This functional difference may have significant implications in infectious and inflammatory diseases.

Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.