A novel subset of lung tissue-resident memory CD4 T cells generated by influenza virus infection (MUC1P.903)

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Abstract We recently identified a late IL-2-dependent ‘checkpoint’ during the effector phase of the T cell response against influenza A virus (IAV) that is required for the generation of most long-lived CD4 T cell memory. Here, we describe a novel subset of IL-2- and IL-7-independent IAV-specific memory CD4 T cells that survive only in the lung (the site of IAV infection). These cells (i) are shielded from labeling by fluorescent anti-CD4 antibodies administered intravenously, (ii) express a CD69high, CD127low surface phenotype, and (iii) are highly functional upon re-stimulation both in terms of cytokine production and the ability to rapidly activate dendritic cells. These characteristics are consistent with recently described ‘tissue-resident’ memory T cells (Trm). In contrast to most described CD8+ Trm populations, the IAV-specific CD4+ Trm are not CD103high, and do not require TGF-β signaling for their generation. We show that this novel CD4+ Trm subset survives poorly upon adoptive transfer to unmanipulated hosts, suggesting that this Trm subset is adapted to survive in a unique non-lymphoid niche. Transcriptional analysis further supports this hypothesis as broad differences distinguish Trm from conventional memory CD4 T cells present in the lung. In summary, our studies identify a population of IAV-specific Trm CD4 T cells that develops independently of signals required for the generation of virtually all other subsets of CD4+ memory T cells.