Figure 1. (A) Following intravaginal infection with HSV-2; stimulation with pathogenic symptomatic and protective asymptomatic human epitopes, expressed by the virus, greatly contributes to development of HSV-specific memory CD8⁺ T cell subsets, with either VM-resident effector memory (T_EM) and tissue-resident memory (T_RM) or lymphoid resident central memory CD8⁺ T cells (T_CM). (See text for details). We hypothesize that virus derived symptomatic epitopes boost primarily CD8⁺ T_CM, that reside primarily in the secondary lymphoid tissues, such as GT-DLN, which, once re-activated, re-circulate through the bloodstream into the vaginal mucosa (VM). In contrast, virus derived asymptomatic epitopes boost primarily VM-resident CD8⁺ T_EM/T_RM that are retained in the mucosal site of viral entry. (B). Anatomic-distribution, phenotypic, and functional characteristics of HSV-specific symptomatic central memory CD8⁺ T cells (T_CM) vs. asymptomatic effector memory (T_EM) CD8⁺ T-cells induced following intravaginal infection with HSV-2. Intra-vaginal (VAG) infection with HSV-2 bearing both symptomatic or asymptomatic epitopes prime naïve T cells into effector T cells to clear the virus infection while simultaneously generating memory CD8⁺ T cells to protect against subsequent encounter with the virus following re-infection or reactivation from latently infected sensory ganglia. We hypothesize that after the clearance of the virus, there is an optimum equilibrium between SLECs (IL7R^lowKLRG1^high) and MPECs (IL7R^highKLRG1^low) cells derived from an early effector cells (EECs, IL7R^lowKLRG1^low), which then transit to 2 main categories of memory CD8⁺ T cells: T_CM CD8⁺ T cells specific to symptomatic epitopes and T_EM CD8⁺ T cells specific to asymptomatic epitopes. T_EM CD8⁺ T-cells are mainly retained in the vaginal mucosa (see text for detail).