CD4tissue-resident memory T cells and their role in immunity.

CD4tissue-resident memory T (T) cells are essential for immune protection in the lungs, providing rapid responses against respiratory pathogens. Unlike circulating memory T cells, CD4Tcells 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 CD8Tcells are well studied, the role of CD4Tcells in immunity remains less defined and is the focus of this review. Distinct subsets, based on the effector T1, T2, T17 and T follicular helper (T)-like tissue-resident helper (T) cells, contribute to antiviral, antibacterial, antifungal and vaccine-induced immunity. CD4Tcells 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 CD4Tcells, 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 CD4Tcells, highlighting their potential for respiratory pathogen control. In this review, we focus on CD4Tcells, their differentiation, maintenance and role, especially in the lungs.