High-quality CMV-specific CD4+ Memory is Enriched in the Lung Allograft and is Associated with Mucosal Viral Control

The maintenance of CMV-specific T cell memory in lung transplant recipients (LTRs) is critical for host defense and allograft durability, particularly in donor(+) /recipient(-) (D(+) R(-) ) individuals who demonstrate increased mortality. We studied CD4(+) and CD8(+) CMV-specific memory responses to phosphoprotein 65 (pp65) in a prospective cohort of 18 D(+) R(-) LTRs, from bronchoalveolar lavage (BAL)-obtained lung mononuclear cells (LMNC) and PBMC. Unexpectedly, pp65-specific CD4(+) and CD8(+) IFN-γ memory responses from LMNC were similar, in contrast to persistent CD8(+) predominance in PBMC. Unlike the pulmonary CD8(+) predominance during acute primary infection, compartmental equalization occurred in the CMV-specific CD8(+) memory pool during chronic infection, whereas CMV-specific CD4(+) memory was enriched in the bronchoalveolar space. Moreover, CMV-specific CD4(+) memory T cells with multifunctional production of IFN-γ, TNF-α, IL-2 and MIP-1β were significantly increased in LMNCs, in contrast to similar intercompartmental CD8(+) memory function. Moreover, the absolute number of CMV-specific CD4(+) IFN-γ(+) memory cells in BAL was significantly increased in LTRs exhibiting viral control compared to those with CMV early antigen positivity. Collectively, these data demonstrate both preferential distribution and functional quality of CMV-specific CD4(+) memory in the lung allograft during chronic infection, and show an important association with CMV mucosal immunity and viral control.