CD4⁺ 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_H1, T_H2, T_H17 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.