CD4⁺ T Cell Help Guides Formation of CD103⁺ Lung-Resident Memory CD8⁺ T Cells during Influenza Viral Infection

Tissue-resident memory T (Trm) cells provide enhanced protection against infection at mucosal sites. Here we found that CD4⁺ Tcells are important for the formation of functional lung-resident CD8⁺ Tcells after influenza virus infection. In the absence of CD4⁺ Tcells, CD8⁺ Tcells displayed reduced expression of CD103 (Itgae), were mislocalized away from airway epithelia, and demonstrated an impaired ability to recruit CD8⁺ Tcells to the lung airways upon heterosubtypic challenge. CD4⁺ Tcell-derived interferon-γ was necessary for generating lung-resident CD103⁺ CD8⁺ Trm cells. Furthermore, expression of the transcription factor T-bet was increased in "unhelped" lung Trm cells, and areduction in T-bet rescued CD103 expression in the absence of CD4⁺ Tcell help. Thus, CD4⁺ Tcell-dependent signals are important to limit expression of T-bet and allow for the development of CD103⁺ CD8⁺ Trm cells in the lung airways following respiratory infection.