A Critical Role for OX40 in T Cell–mediated Immunopathology during Lung Viral Infection

Abstract

Respiratory infections are the third leading cause of death worldwide. Illness is caused by pathogen replication and disruption of airway homeostasis by excessive expansion of cell numbers. One strategy to prevent lung immune–mediated damage involves reducing the cellular burden. To date, antiinflammatory strategies have affected both antigen-specific and naive immune repertoires. Here we report a novel form of immune intervention that specifically targets recently activated T cells alone. OX40 (CD134) is absent on naive T cells but up-regulated 1–2 d after antigen activation. OX40–immunoglobulin fusion proteins block the interaction of OX40 with its ligand on antigen-presenting cells and eliminate weight loss and cachexia without preventing virus clearance. Reduced proliferation and enhanced apoptosis of lung cells accompanied the improved clinical phenotype. Manipulation of this late costimulatory pathway has clear therapeutic potential for the treatment of dysregulated lung immune responses.

OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis

“…Furthermore, redundancy in such late costimulators that act at the same stage as OX40/OX40L (such as 4-1BB/4-1BBL) would provide the signals required for maintenance of sufficient inflammation and the development of immunological memory (32, 34, 39, 40). Interestingly, OX40 or OX40L blockade is actually beneficial in infectious diseases associated with immunopathology, such as virally induced myocarditis (41), respiratory viruses (34), and polymicrobial sepsis (42), which are significant complications of current treatment strategies for arthritis. For these reasons, blockade of late T-cell costimulators and their receptors should be tested in humans.…”

Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses

“…OX40 Ϫ/Ϫ CD8 cells showed a more pronounced defect in producing TNF compared with IFN-␥, indicating that the OX40 signal may differentially target this cytokine in fully activated CD8 T cells. Of note, a previous report showed that blocking OX40L with OX40-Ig reduced TNF production from CD8 T cells after influenza virus infection (55), and more recently Ito et al (56) showed that OX40 signaling selectively promoted TNF secretion in human CD4 T cells in vitro. Thus, the regulation of TNF synthesis by OX40 may be common to CD4 and CD8 T cells in various inflammatory circumstances.…”

CD4 T cell responses to influenza infection

“…It is not known to what extent CD4 cells contribute to lung immunopathology after influenza infection, however, it is known that Th2 cells do not protect against lethal influenza infection [51] and the reason for this may be due to increased pathology mediated by the type 2 cytokines, IL-4 and IL-5 leading to eosinophilia. Recently, it has been shown that blocking the OX40-OX40L costimulatory pathway can lead to decreased T cell influx into the lungs and diminished immunopathology after influenza infection [54]. It remains to be determined if CD4 and CD8 cells contribute equally to immunopathology after infection with more virulent strains of influenza.…”