CD4<sup>+</sup> tissue-resident memory T cells and their role in immunity

CD4 + tissue-resident memory T (T RM ) cells are essential for immune protection in the lungs, providing rapid responses against respiratory pathogens. Unlike circulating memory T cells, CD4 + T RM cells persist in the tissue parenchyma and possibly inducible lymphoid tissues, where they facilitate pathogen clearance through cytokine production and interactions with local immune cells. While CD8 + T RM cells are well studied, the role of CD4 + T RM cells in immunity remains less defined and is the focus of this review. Distinct subsets, based on the effector T H 1, T H 2, T H 17 and T follicular helper (T FH )-like tissue-resident helper (T RH ) cells, contribute to antiviral, antibacterial, antifungal and vaccine-induced immunity. CD4 + T RM cells play a key role in infections, enhancing immune responses and supporting antibody production. However, they are also implicated in chronic inflammation, allergies and fibrosis. Given their importance, vaccines aiming to elicit lung-resident CD4 + T RM cells, particularly via mucosal delivery, have shown promise in inducing long-term protective immunity. Intranasal vaccination strategies, such as live-attenuated influenza virus and tuberculosis vaccines, have successfully generated CD4 + T RM cells, highlighting their potential for respiratory pathogen control. In this review, we focus on CD4 + T RM cells, their differentiation, maintenance and role, especially in the lungs.