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Fate induction through asymmetric T cell division is modulated by chimeric antigen receptor costimulatory domains To investigate how different costimulatory domains influence the initial cell fate decisions in CAR T cells, we first examined the expression patterns of 4-1BB (BBζ) and CD28 (28ζ) CARs (Extended Data Fig. 1a). The 28ζ CARs consistently displayed higher surface expression levels and a strikingly more homogeneous expression pattern compared to BBζ CARs, which showed a characteristic broad distribution (Fig. 1a). This distinction was not a function of differential transduction efficiency, because both constructs achieved comparable transduction rates (Fig. 1b). The difference appeared to be intrinsic to the costimulatory domain itself, because messenger RNA electroporation (which bypasses lentiviral integration site variability) reproduced the same pattern: a narrow, homogeneous peak for 28ζ and a broad distribution for BBζ (Fig. 1a). Across multiple donors, the median fluorescence intensity was consistently higher for 28ζ CARs at similar transduction efficiencies and expression was notably more homogeneous, as demonstrated by the decreased coefficient of variation of CAR staining (Fig. 1b). Importantly, this costimulatory, domain-dependent expression pattern is a generalizable phenomenon that extends well beyond the CARs used in this study. Multiple independent laboratories have observed the same distinction (homogeneous, high-level expression for CD28 CARs and broader, more heterogeneous expression for 4-1BB CARs) across different target... https://www.nature.com/articles/s41590-026-02548-w