CD4 tissue-resident memory T cells and their role in immunity.

CD4 tissue-resident memory T (T) cells are essential for immune protection in the lungs, providing rapid responses against respiratory pathogens. Unlike circulating memory T cells, CD4 T 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 cells are well studied, the role of CD4 T cells 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. CD4 T 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 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 cells, highlighting their potential for respiratory pathogen control. In this review, we focus on CD4 T cells, their differentiation, maintenance and role, especially in the lungs.