Role of mucosal chemokines in the development of tissue-resident CD4+ and CD8+ TRM cells to fend off herpes simplex infections

The mucosal immune system represents the largest and most significant component of the immune network, providing critical defense against infectious pathogens at mucosal surfaces. Mucosal surfaces include the oronasal cavities, ocular surface, gastrointestinal tract, respiratory tract, and reproductive tract. Mucosal tissue-resident memory (T_RM) CD4⁺ and CD8⁺ T_RM cells serve as sentinels and critical mediators of adaptive mucosal immunity, continuously trafficking to mucosal tissues to surveil and clear invading pathogens. The development of mucosal CD4⁺ and CD8⁺ T_RM cells is regulated by mechanisms distinct from those governing circulating effector memory (T_EM) and central memory (T_CM) T cells. Current models suggest that the generation, retention, and expansion of CD4⁺ and CD8⁺ T_RM cells within mucosal tissues are coordinated by mucosa-specific chemokines and adhesion molecules, thereby facilitating their selective homing and retention at mucosal surfaces. Among the 48 known chemokines, CXCL17, CCL25, CCL28, and CXCL14 have emerged as major key mucosal-specific chemokines that orchestrate mucosal CD4⁺ and CD8⁺ T_RM cell responses. This review (1) describes the roles of these four major mucosal chemokines in shaping T_RM cell-mediated immunity against mucosal pathogens, with a focus on herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), two infectious pathogens of the ocular and genital mucosae and (2) discuss harnessing these mucosal chemokine-receptor axes to develop a tissue-targeted Prime/Pull/Keep (PPK) herpes vaccine and immunotherapeutic strategies.