Nicotine Suppresses Human Memory Th Cell Subsets With Preferential Effects on Central Memory Th Cells in an α7...

Memory T helper (Th) cells sustain protective recall responses but can also drive chronic inflammation, necessitating precise regulation of their effector programs. Although Th cells produce acetylcholine (ACh) and express nicotinic acetylcholine receptors (nAChRs), the contribution of nAChRs to human memory Th function across central (Tcm) and effector (Tem) subsets is poorly defined. We examined the effect of nicotine and GTS-21, a compound previously described as targeting α7nAChR, on total memory Th cells and purified Tcm and Tem from healthy participants. Nicotine or GTS-21 diminished IFN-γ, IL-4, and IL-17A secretion, downregulated TBX21, GATA3, and RORC, and reduced NF-κB p65 phosphorylation in total memory Th cells. Disruption of CHRNA7 abolished nicotine-mediated suppression but did not eliminate the inhibitory effects of GTS-21. Within CCR7-defined subsets, nicotine and GTS-21 lowered Th1/Th2/Th17 frequencies in Tcm, but not in Tem. In purified subsets, nicotine suppressed IFN-γ, IL-4, IL-17A, IL-21, BCL6, and CD40L selectively in Tcm, whereas GTS-21 suppressed them in both Tcm and Tem. Collectively, nicotine engages an α7nAChR-dependent checkpoint that preferentially regulates Tcm responses, while GTS-21 exerts broader suppressive effects not fully explained by α7nAChR loss. This cholinergic checkpoint in Tcm may limit Tfh-associated help and pathogenic recall responses in immune-mediated disease.