Pluripotent allospecific CD8⁺ effector T cells traffic to lung in murine obliterative airway disease

Long-term success in lung transplantation is limited by obliterative bronchiolitis, whereas T cell effector mechanisms in this process remain incompletely understood. Using the mouse heterotopic allogeneic airway transplant model, we studied T cell effector responses during obliterative airways disease (OAD). Allospecific CD8⁺IFN-γ⁺ T cells were detected in airway allografts, with significant coexpression of TNF-α and granzyme B. Therefore, using IFN-γ as a surrogate marker, we assessed the distribution and kinetics of extragraft allospecific T cells during OAD. Robust allospecific IFN-γ was produced by draining the lymph nodes, spleen, and lung mononuclear cells from allograft, but not isograft recipients by Day 14, and significantly decreased by Day 28. Although the majority of allospecific T cells were CD8⁺, allospecific CD4 ⁺ T cells were also detected in these compartments, with each employing distinct allorecognition pathways. An influx of pluripotent CD8 ⁺ effector cells with a memory phenotype were detected in the lung during OAD similar to those seen in the allografts and secondary lymphoid tissue. Antibody depletion of CD8⁺ T cells markedly reduced airway lumen obliteration and fibrosis at Day 28. Together, these data demonstrate that allospecific CD8⁺ effector T cells play an important role in OAD and traffic to the lung after heterotopic airway transplant, suggesting that the lung is an important immunologic site, and perhaps a reservoir, for effector cells during the rejection process.