4-1BB Regulates Effector CD8 T Cell Accumulation in the Lung Tissue through a TRAF1-, mTOR-, and Antigen-Dependent Mechanism to Enhance Tissue-Resident Memory T Cell Formation during Respiratory Influenza Infection

Abstract

The TNFR superfamily member 4-1BB is important in the establishment of tissue-resident memory T cells (Trm) in the lung tissue following influenza infection. Moreover, supraphysiological boosting of 4-1BB in the airways during the boost phase of a prime-boost immunization regimen increases the long-lived Trm population, correlating with increased protection against heterotypic challenge. However, little is known about how 4-1BB contributes to the establishment of the lung Trm population. In this study, we show that effects of 4-1BB on lung Trm accumulation are already apparent at the effector stage, suggesting that the major role of 4-1BB in Trm formation is to allow persistence of CD8 T effector cells in the lung as they transition to Trm. Using supraphysiological stimulation of 4-1BB in the boost phase of a prime-boost immunization, we show that the effect of 4-1BB on Trm generation requires local delivery of both Ag and costimulation, is inhibited by rapamycin treatment during secondary CD8 effector T cell expansion, and is dependent on the signaling adaptor TRAF1. The decrease in lung Trm following early rapamycin treatment is accompanied by increased circulating memory T cells, as well as fewer effectors, suggesting a role for mammalian target of rapamycin (mTOR) in the formation of Trm through effects on the accumulation of effector precursors. Taken together, these data point to an important role for 4-1BB, TRAF1, and mTOR in the persistence of CD8 effector T cells in the lung parenchyma, thereby allowing the transition to Trm.

Formation and Maintenance of Tissue Resident Memory CD8+ T Cells after Viral Infection

“…Although these papers did not look at the function of CD49a, in a gut model of T RM , TGF−β was shown to be important for expression of CD49 on a4b7+ gut T RM [37] In an influenza infection model, another stimulatory signal for T RM formation comes from 4-1BB [40]. 4-1BB is a TNF family receptor and endogenous signals from antigen-bearing 4-1BB ligand expressing cells in the tissue enhance T RM formation while exogenous administration of 4-1BB ligand further expands the number of T RM formed [40].…”

GITR differentially affects lung effector T cell subpopulations during influenza virus infection

“…TNFR family members such as CD27, 4‐1BB, OX40, and glucocorticoid‐induced TNFR‐related protein (GITR) are up‐regulated upon T cell activation and play important roles in controlling the magnitude and duration of T cell responses during viral infections . Moreover, TNF/TNFR family members including LIGHT, OX40, 4‐1BB, and GITR have been shown to contribute to accumulation of effector T cells and Trm formation in the tissues . Recent data show that during viral infection the TNF superfamily ligands, CD70, 4‐1BBL, OX40L, and GITR ligand (GITRL) are coordinately induced by IFN‐I on monocyte‐derived cells with minimal expression on conventional dendritic cells .…”

Identification of Differentially Expressed Genes and Enriched Pathways in SARS-CoV-2/ COVID-19 using Bioinformatics Analysis

“…Hub gene CH25H was liable for progression of porcine reproductive and respiratory syndrome virus infection [145], but this gene may be involved in the advancement of SARS-CoV-2 infection. Hub genes such as TRAF1 [146], IFIT5 [147], CFTR (CF transmembrane conductance regulator) [148] and SMARCA2 [149] were key for progression of in uenza viral infection; however, these genes may be linked with the progression of SARS-CoV-2 infection. Hub gene SAP30 was responsible for the advancement of Rift Valley fever virus infection [150], but this gene may be vital for the advancement of SARS-CoV-2 infection.…”