Endogenous 4-1BB Ligand Plays a Critical Role in Protection from Influenza-Induced Disease

Abstract

A critical issue during severe respiratory infection is whether it is the virus or the host response that does the most damage. In this study, we show that endogenous 4-1BBL plays a critical role in protecting mice from severe effects of influenza disease. During mild respiratory influenza infection in which virus is rapidly cleared, the inducible costimulatory receptor 4-1BB is only transiently induced on lung T cells and 4-1BB ligand (4-1BBL) is completely dispensable for the initial CD8 T cell response and mouse survival. In contrast, during more severe respiratory influenza infection with prolonged viral load, 4-1BB expression on lung CD8 T cells is sustained, and 4-1BBL-deficient mice show decreased CD8 T cell accumulation in the lungs, decreased viral clearance, impaired lung function, and increased mortality. Transfer of an optimal number of naive Ag-specific T cells before infection protects wild-type but not 4-1BBL-deficient mice from an otherwise lethal dose of influenza virus. T he CD8 T cells are important mediators of protective immunity to viruses (1). Indeed a strong CD8 T cell response to influenza offers the hope of cross-protective immunity to diverse influenza strains (2, 3). However, there is a concern that too strong an immune response in the lung will cause immune pathology and a worse outcome (4 -6). Upon initial encounter with Ag, T cells commit to programmed expansion, which occurs independently of the continued presence of Ag (7,8). How then does the immune system provide the appropriate level of T cell stimulation for a particular infection? T cells regulate their level of response by integrating signals from the Ag-specific receptor as well as from costimulatory, coinhibitory, and cytokine receptors which in turn influence the initiation, duration, and differentiation of the response (9 -12). The initial activation of T cells requires costimulatory signals from CD28, expressed on resting T cells. In addition, during an on-going immune response, other costimulatory receptors and ligands are up-regulated on the T cells and APCs (13-15). The question arises as to why so many costimulatory receptor ligand pairs have accumulated in the mammalian immune system. Here we provide evidence that the expression of one such costimulatory receptor, 4-1BB, is sustained in response to severe as compared with mild respiratory infection with influenza virus, thereby allowing the immune system to maintain a level of CD8 T cell response appropriate for the severity of the infection.The receptor 4-1BB (CD137) is a member of the TNFR family expressed on Ag-receptor activated T cells (14, 16 -18). In vivo with nonreplicating immunogens, 4-1BB is rapidly and transiently up-regulated on T cells upon immunization, before the first cell division and concomitantly with the expression of the early activation marker CD69 (19). Evidence that 4-1BB can play a role early in the response comes from systemic administration of agonist anti-4-1BB Abs, which can enhance initial antitumor and antiviral T cell responses wi...

Targeting 4-1BB (CD137) to enhance CD8 T cell responses with poxviruses and viral antigens

“…Transient 4-1BB expression likely translated to a brief period of signaling from anti-4-1BB to augment clonal division in the effector cells, but the necessary pro-survival signals may not have been induced that result from extended 4-1BB signaling and that might be needed to allow greater accumulation of memory cells. Our findings are reminiscent of a prior study (Lin et al, 2009) that showed that 4-1BB expression on CD8 T cells was prolonged with respiratory tract infection of a virulent influenza virus compared to a milder influenza virus. This also correlated with a requirement for 4-1BB in the T cell response to the former, whereas 4-1BB was dispensable for the response to the less virulent strain.Similarly, anti-4-1BB was previously shown to enhance primary T cell responses to influenza virus delivered by the non-productive i.p.…”

Modulation of GITR for cancer immunotherapy

“…Interestingly, lack of GITR did not appear to change the percentage of CD8+ T cells that became IFNγ+ [21••]. This finding was similar to a previous one by the same group demonstrating reduced survival of 4-1BB−/− mice challenged with the PR8 strain [22•]. Thus, although GITR and 4-1BB may be similar, they seem to serve non-redundant roles.…”

Gene Therapy for ALI/ARDS

“…Several other less obvious approaches have also been taken to limit inflammation or control immune responses in the lung in response to infection. For example, one group used 4-1BB ligand (4-1BBL) to protect from lung injury caused by influenza infection in the lung 79 . 4-1BBL binds to 4-1BB (CD137), a member of the TNF receptor family expressed on activated T cells that is rapidly up-regulated on T cells following viral infection.…”