A robust immunological memory is critical for the longevity of any vaccine. We have demonstrated CD4+ T stem cell memory (TSCM) in the Thai RV144 HIV-1 vaccine clinical trial. Comparable TSCM were demonstrated in the mucosal vaccination of women, using HIVgp140-HSP70 conjugate administered by the vaginal route. TSCM can be upregulated by recombinant IL-15 or DC membrane associated IL-15 (maIL-15) by a variety of stress agents, such as thermal, oxidative or ionophore, which we studied in vitro. Recombinant IL-15 elicited >3-fold increase and DC maIL-15 >2-fold increase in CD4+ TSCM. Both systemic and mucosal immunization elicited lower TSCM than the in vitro activated cells. Surprisingly, recall of past exposure to immunogens, such as PPD, showed similar increase to PPD as that to the stress agent. This was shown for CD4 proliferative responses, Th1 cytokines and CC chemokines. As both the homeostatic and inflammasome pathways may be stimulated by stress agents, inhibition studies were carried out to validate this for TSCM. Indeed both pathways may be involved in CD4+ T cell proliferation, though the homeostatic pathway is more significant than the inflammasome one. These studies support the concept that stress agents are important in eliciting and maintaining CD4+ TSCM cell longevity in vaccination.