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.

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.