MEK inhibition of T cells is memory stage–dependent, in contrast to calcineurin inhibition. (A) Tacrolimus inhibits T cells in a memory stage–independent fashion. PBMCs from healthy donors (n = 7) were stimulated with SEB in the presence of DMSO as a carrier control, and in the presence of tacrolimus. The extent of cytokine production (either TNFα at left, or IFNγ, right) was expressed with relative suppression expressed as a percentage of the DMSO control assessed within T-cell maturation subsets. Means for the degree of inhibition within progressively differentiated memory subsets are shown, with no significant difference seen across subsets. (B-C) MEK inhibition spares progressively differentiated CD4⁺ and CD8⁺ T cells. As above, the extent of cytokine production (either TNFα at left, or IFNγ, right) was assessed in the presence of the MEK inhibitor U0126 (10 µM, B) or selumetinib (10 μM, C), with relative suppression expressed as a percentage of the DMSO control assessed within T-cell maturation subsets. Means for the degree of inhibition within progressively differentiated memory subsets are shown, demonstrating profound inhibition in naive CD4⁺ and CD8⁺ T cells, with less significant inhibition seen (*P < .05) in each progressively differentiated memory CD4⁺ or CD8⁺ T-cell subset.