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

## TL;DR

This paper reviews how specific mucosal chemokines help CD4+ and CD8+ TRM cells defend against herpes simplex infections in mucosal tissues.

## Contribution

The paper highlights four key mucosal chemokines and their role in shaping TRM cell immunity against HSV-1 and HSV-2.

## Key findings

- CXCL17, CCL25, CCL28, and CXCL14 are major mucosal chemokines that regulate TRM cell responses.
- These chemokines facilitate the homing and retention of TRM cells at mucosal surfaces.
- They are proposed for use in developing a tissue-targeted PPK herpes vaccine strategy.

## Abstract

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 (TRM) CD4+ and CD8+ TRM 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+ TRM cells is regulated by mechanisms distinct from those governing circulating effector memory (TEM) and central memory (TCM) T cells. Current models suggest that the generation, retention, and expansion of CD4+ and CD8+ TRM 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+ TRM cell responses. This review (1) describes the roles of these four major mucosal chemokines in shaping TRM 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.