Table 2.

Co-receptors used the most often in CAR design in CAR-NK cell studies.

Co-Receptor	Function in a CAR Particle	Description
CD28	Co-stimulation	Essential for T cell activation. Improves anti-tumor activity and persistence at a low effector to target ratio. Induces IL-2 production and CD4+ T cell expansion. In CAR-T cells, induces central and effector memory phenotypes. Responsible for recruitment of Tregs limiting CAR-T activity. Not expressed in unmodified NK cells. Used as co-stimulatory receptor with CD3ζ in CAR-NK cells, gives superior results than CD3ζ.CAR alone.
CD3ζ	Signaling	Expressed in unmodified NK and T cells. Used in both CAR-T and CAR-NK cells. Contains three ITAM motifs for signal transduction. Initiates cell killing. In dimers, transmits CD16 signal for ADCC initiation. Stimulates proliferation.
DAP10	Co-stimulation	An adaptor molecule. Does not have an ITAM motif, unable to transduce the signal. Expressed in unmodified T and NK cells. Interacts with activating NKG2D receptor. Involved in NK cells activation.
DAP12	Co-stimulation Signaling	An adaptor molecule. Has one ITAM motif. Superior signaling potential to CD3ζ. Interacts with NKG2C, NKp44, KIR receptors. Not expressed in unmodified T cells. Involved in NK cells activation.
2B4	Co-stimulation	Expressed in unmodified NK cells. In CAR-NK cells, induces cytokine production and invasiveness.
4-1BB	Co-stimulation	Essential for T cell proliferation and survival. Enhances the proliferation of CD8+ and CD4+ T cells. Induces IL-2 production. Prolongs T cell division. Prolongs CAR-T cell persistence. Not expressed in unmodified NK cells. Used as co-stimulatory receptor with CD3ζ in CAR-NK cells. Gives superior results than CD3ζ.CAR alone.