Allergen exposure functionally alters influenza-specific CD4⁺ Th1 memory cells in the lung

CD4⁺ lung-resident memory T cells (T_RM) generated in response to influenza infection confer effective protection against subsequent viral exposures. Whether these cells can be altered by environmental antigens and cytokines released during heterologous, antigen-independent immune responses is currently unclear. We therefore investigated how influenza-specific CD4⁺ Th1 T_RM in the lung are impacted by a subsequent Th2-inducing respiratory house dust mite (HDM) exposure. Although naïve influenza-specific CD4⁺ T cells in the lymph nodes do not respond to HDM, influenza-specific CD4⁺ T_RM in the lungs do respond to a subsequent allergen exposure by decreasing expression of the transcription factor T-bet. This functional alteration is associated with decreased IFN-γ production upon restimulation and improved disease outcomes following heterosubtypic influenza challenge. Further investigation revealed that ST2 signaling in CD4⁺ T cells during allergic challenge is necessary to induce these changes in lung-resident influenza-specific CD4⁺ T_RM. Thus, heterologous antigen exposure or ST2-signaling can drive persistent changes in CD4⁺ Th1 T_RM populations and impact protection upon reinfection.