HOXA10 orchestrates rapid memory T cell activation via a DNAJB14-KCNH2-calcium axis

Memory T cells mount faster, stronger responses to secondary antigen, yet how their activation speed and threshold are set remains incompletely understood. Here we show that HOXA10 is an activation-induced transcription factor that calibrates recall responsiveness in CD4⁺ T cells. HOXA10 is upregulated with anti-CD3/CD28 stimulation and enriched in the memory compartment. Although HOXA10 deletion does not alter the formation or maintenance of memory subsets, it elevates the recall threshold and blunts secondary responses both ex vivo and in a Listeria monocytogenes infection model. Mechanistically, HOXA10 transcriptionally upregulates DNAJB14; it in turn maintains the potassium channel KCNH2 at the protein level. Disrupting HOXA10 or DNAJB14 diminishes TCR-evoked Ca²⁺ influx, whereas ectopic DNAJB14 or KCNH2 restores Ca²⁺ entry toward wild-type levels. These findings define a previously undescribed HOXA10/DNAJB14/KCNH2 pathway that links transcriptional control to ion-channel homeostasis, thereby tuning the activation threshold and pace of memory CD4⁺ T-cell responses and suggesting a tractable axis for modulating immunity in infection and autoimmunity.