Regulation of CD8+ T cell tissue residency following influenza infection

Abstract

Durable CD8+ T cell memory is a defining feature of adaptive immunity to pathogens. Among memory CD8+ T cell subsets, tissue-resident memory (TRM) cells are locationally positioned within nonlymphoid tissues to respond rapidly to secondary antigen encounter. The generation of CD8+ TRM is known to require antigen and specific cytokine cues. Although CD8+ TRM constitutively express the coinhibitory receptor PD-1 in the absence of antigen stimulation, the functional significance of PD-1 in regulating CD8+ TRM differentiation and function remains unclear. Here, we investigated the regulatory role of PD-1 in CD8+ T cell differentiation into TRM following infection with influenza virus, which targets the lungs and nasal cavity. Genetic deletion of PD-1 in virus-specific CD8+ T cells resulted in significant expansion of virus-specific effector CD8+ T cells, yet compromised the establishment of durable, functional CD8+ TRM in the lungs and nasal mucosa following infection. Transcriptional studies suggest that PD-1 loss altered CD8+ T cell differentiation in the lymph node by altering the duration of the G1 phase of the cell cycle and modifying the utilization of pioneer transcription factors (TFs) that regulate chromatin accessibility. Loss of PD-1 impaired the ability of effector CD8+ T cells to express the adhesion molecule CD103 in response to TGF-β signaling. In addition, PD-1 KO CD8+ T cells had a reduced ability to downregulate the tissue egress receptors S1PR1 and CCR7 following entry into infected tissue. During the memory phase, PD-1 KO CD8+ T cells in the lung expressed TFs that antagonize tissue residency, including Klf2 and TCF-1/Tcf7. The deleterious impact of PD-1 deletion on TRM formation was partially tissue-dependent, with a more profound reduction in TRM accumulation in the lungs than the nasal mucosa. These two tissues display distinct viral infection kinetics, differing requirements for TRM formation, and distinct capacities to support life-long CD8+ TRM. These factors, individually or in combination, may determine the impact of PD-1 deletion on CD8+ T cell fate in each tissue. Collectively, these findings support a model in which PD-1 deficiency enhances CD8+ T cell proliferation in draining lymph nodes but compromises their adaptability within infected tissues. However, the consequences of PD-1 loss are also shaped by the specific characteristics of the infected tissue microenvironment.