RT Journal Article SR Electronic T1 Constitutive CD8 expression drives innate CD8+ T-cell differentiation via induction of iNKT2 cells JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202000642 DO 10.26508/lsa.202000642 VO 3 IS 2 A1 Satoshi Kojo A1 Michiko Ohno-Oishi A1 Hisashi Wada A1 Sebastian Nieke A1 Wooseok Seo A1 Sawako Muroi A1 Ichiro Taniuchi YR 2020 UL https://www.life-science-alliance.org/content/3/2/e202000642.abstract AB Temporal down-regulation of the CD8 co-receptor after receiving positive-selection signals has been proposed to serve as an important determinant to segregate helper versus cytotoxic lineages by generating differences in the duration of TCR signaling between MHC-I and MHC-II selected thymocytes. By contrast, little is known about whether CD8 also modulates TCR signaling engaged by the non-classical MHC-I–like molecule, CD1d, during development of invariant natural killer T (iNKT) cells. Here, we show that constitutive transgenic CD8 expression resulted in enhanced differentiation of innate memory-like CD8+ thymocytes in both a cell-intrinsic and cell-extrinsic manner, the latter being accomplished by an increase in the IL-4–producing iNKT2 subset. Skewed iNKT2 differentiation requires cysteine residues in the intracellular domain of CD8α that are essential for transmitting cellular signaling. Collectively, these findings shed a new light on the relevance of CD8 down-regulation in shaping the balance of iNKT-cell subsets by modulating TCR signaling.