Influenza-specific CD4+ Th1 memory cells in the lung can be functionally altered by allergen exposure

Abstract

CD4+ lung-resident memory T cells (Trm) 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 Trm 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 secondary lymphoid organs do not respond to HDM, influenza-specific CD4+ Trm in the lungs do respond to a subsequent allergen exposure by altering their phenotype and functional capacity. Changes in transcription factor expression in this population persisted upon heterosubtypic influenza challenge and was associated with decreased morbidity, viral load, and pro-inflammatory cytokine expression in the lung. Further investigation revealed that respiratory cysteine protease or rIL-33 administration was sufficient to induce these changes in the lung-resident influenza-specific CD4+ Trm population. Thus, heterologous antigen exposure or IL-33 release can drive persistent alterations in CD4+ Th1 Trm populations.