Abstract
Tissue-resident memory CD8+ T (TRM) cells that develop in the epithelia at portals of pathogen entry are important for improved protection against re-infection. CD8+ TRM cells within the skin and the small intestine are long-lived and maintained independently of circulating memory CD8+ T cells. In contrast to CD8+ TRM cells at these sites, CD8+ TRM cells that arise after influenza virus infection within the lungs display high turnover and require constant recruitment from the circulating memory pool for long-term persistence. The distinct characteristics of CD8+ TRM cell maintenance within the lungs may suggest a unique program of transcriptional regulation of influenza-specific CD8+ TRM cells. We have previously demonstrated that the transcription factors Hobit and Blimp-1 are essential for the formation of CD8+ TRM cells across several tissues, including skin, liver, kidneys, and the small intestine. Here, we addressed the roles of Hobit and Blimp-1 in CD8+ TRM cell differentiation in the lungs after influenza infection using mice deficient for these transcription factors. Hobit was not required for the formation of influenza-specific CD8+ TRM cells in the lungs. In contrast, Blimp-1 was essential for the differentiation of lung CD8+ TRM cells and inhibited the differentiation of central memory CD8+ T (TCM) cells. We conclude that Blimp-1 rather than Hobit mediates the formation of CD8+ TRM cells in the lungs, potentially through control of the lineage choice between TCM and TRM cells during the differentiation of influenza-specific CD8+ T cells.
Highlights
Long-term memory of previously encountered pathogens is crucial to enable enhanced responses of our body’s immune defenses in future encounters with the same pathogen
Influenza virus infection gave rise to a substantial CD69+ CD8+ TRM cell population in the lung, which partially expressed CD103 (Figure 1A). This population was nearly absent in lungs from naïve mice, indicating that the vast majority of CD8+ TRM cells were a direct result of influenza virus infection
Transcriptional profiling of CD69+ and CD69− memory CD8+ T cells isolated from lungs of HKx31-immune mice by RNA sequencing confirmed the resident phenotype of the CD69+ CD8+ T cell population arising after influenza virus infection (Figure 1B)
Summary
Long-term memory of previously encountered pathogens is crucial to enable enhanced responses of our body’s immune defenses in future encounters with the same pathogen. While CD8+ TRM cells in most tissues are long-lived and self-sustaining [2, 16], the virus-specific CD8+ TRM cell population in the lungs declines over time after pulmonary infection, which coincides with waning of heterosubtypic immunity to influenza virus [5, 14, 17]. The mechanisms underlying this limited longevity of lung CD8+ TRM cells are not fully understood. Tissue residency might be differentially regulated at the transcriptional level for CD8+ T cells in the lung compared to other organs
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