Differential CMV-specific CD8⁺ effector T cell responses in the lung allograft predominate over the blood during human primary infection

Acquisition of T cell responses during primary CMV infection in lung transplant recipients (LTRs) appear critical for host defense and allograft durability, with increased mortality in donor⁺/recipient^- (D⁺R^-) individuals. In 15 D⁺R^- LTRs studied, acute primary CMV infection was characterized by viremia in the presence or absence of pneumonitis, with viral loads higher in the lung airways/allograft compared with the blood. A striking influx of CD8⁺ T cells into the lung airways/allograft was observed, with inversion of the CD4⁺:CD8⁺ T cell ratio. De novo CMV-specific CD8 ⁺ effector frequencies in response to pooled peptides of pp65 were strikingly higher in lung mononuclear cells compared with the PBMC and predominated over IE1-specific responses and CD4⁺ effector responses in both compartments. The frequencies of pp65-specific cytokine responses were significantly higher in lung mononuclear cells compared with PBMC and demonstrated marked contraction with long-term persistence of effector memory CD8⁺ T cells in the lung airways following primary infection. CMV-tetramer⁺CD8⁺ T cells from PBMC were CD45RA ^-during viremia and transitioned to CD45RA⁺ following resolution. In contrast, CMV-specific CD8⁺ effectors in the lung airways/allograft maintained a CD45RA^- phenotype during transition from acute into chronic infection. Together, these data reveal differential CMV-specific CD8⁺ effector frequencies, immunodominance, and polyfunctional cytokine responses predominating in the lung airways/allograft compared with the blood during acute primary infection. Moreover, we show intercompartmental phenotypic differences in CMV-specific memory responses during the transition to chronic infection.