Changes in HCMV immune cell frequency and phenotype are associated with chronic lung allograft dysfunction

Area of Science:

• Immunology
• Transplantation Medicine
• Virology

Background:

• Human cytomegalovirus (HCMV) infection is a significant risk factor for chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs).
• The intricate relationship between HCMV and allograft rejection remains incompletely understood.
• Effective treatments to reverse CLAD are lacking, highlighting the need for early predictive biomarkers.

Purpose of the Study:

• To investigate human cytomegalovirus (HCMV) immunity in LTRs who subsequently develop CLAD.
• To quantify and phenotype anti-HCMV CD8+ T cell responses (HLA-A2pp65 and HLA-EUL40) in LTRs with CLAD versus stable grafts.
• To examine the homeostasis of immune cell subsets post-primary HCMV infection in relation to CLAD development.

Main Methods:

• Quantification and phenotyping of HLA-A2pp65 and HLA-EUL40 restricted anti-HCMV CD8+ T cell responses.
• Analysis of immune cell subsets including B cells, CD4 T cells, CD8 T cells, NK cells, and γδT cells.
• Comparison of immune responses and cell subset homeostasis between LTRs developing CLAD and those with stable grafts.

Main Results:

• Reduced frequency of HLA-EUL40 CD8+ T cell responses in LTRs with CLAD compared to stable LTRs (21.7% vs. 55%).
• Similar detection rates for HLA-A2pp65 CD8+ T cells in both CLAD and stable groups (47.8% vs. 45%).
• Altered immunophenotype of HLA-EUL40 CD8+ T cells in CLAD patients (decreased CD56, increased PD-1) and distinct changes in NK and γδT cell subsets.

Conclusions:

• CLAD is associated with significant alterations in anti-HCMV immune responses.
• Dysfunctional HCMV-specific HLA-E-restricted CD8+ T cells and altered immune cell distribution (NK, γδT) represent an early immune signature for CLAD in HCMV+ LTRs.
• This immune signature may facilitate early monitoring and risk stratification of LTRs for CLAD.