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Comparative Study
. 2005 Jun 20;201(12):1999-2010.
doi: 10.1084/jem.20042408.

Repertoire, diversity, and differentiation of specific CD8 T cells are associated with immune protection against human cytomegalovirus disease

Karim Sacre  1 , Guislaine Carcelain, Nathalie Cassoux, Anne-Marie Fillet, Dominique Costagliola, Daniel Vittecoq, Dominique Salmon, Zahir Amoura, Christine Katlama, Brigitte Autran
Affiliations
Comparative Study

Repertoire, diversity, and differentiation of specific CD8 T cells are associated with immune protection against human cytomegalovirus disease

Karim Sacre et al. J Exp Med. .

Abstract

To determine the correlates of immune recovery from active human CMV (HCMV) disease, we compared the antigenic repertoire, diversity, magnitude, and differentiation of HCMV-specific CD8+ T cells in HIV-HCMV coinfected subjects with no, cured, or active HCMV disease and in healthy HIV-negative HCMV-positive controls. ELISPOT-IFN-gamma assays using peptide pools spanning the pp65 and immediate early 1 (IE1) HCMV proteins showed that HCMV-specific CD8+ T cells had a significantly broader antigenic repertoire and greater diversity in HIV-positive patients controlling HCMV replication than in those with active HCMV disease, but the magnitude of the CD8 T cell response did not differ between the different groups. HCMV-specific T cells mainly were focused against IE1 during the short-term recovery from retinitis, and switched toward pp65 during long-term recovery. HCMV-specific T cells displaying an "early" (CD8+CD27+CD28+) and "intermediate" (CD8+CD27-CD28+) differentiation phenotype were increased significantly during long-term recovery compared with other HIV-positive patients and were nearly undetectable during active HCMV disease. HCMV-specific T cells with a "late" (CD8+CD27-28-) differentiation phenotype predominated in all cases. Therefore, restoration of immune protection against HCMV after active HCMV disease in immunodeficient individuals is associated with enlarged repertoire and diversity, and with early differentiation of virus-specific CD8+ T cells, thus defining immune correlates of protection against diseases caused by persistent viruses.

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Figures

Figure 1.
Figure 1.
Broader antigenic repertoire of HCMV-specific CD8+ T cell responses in HIV-positive subjects with controlled HCMV replication or recovering from AHCMV infection, compared with HIV-negative (HN) healthy individuals and patients who had uncontrolled HCMV replication. The number of distinct pp65 and IE1 pools of peptides detected by ELISPOT assay at least once, by group. Each bar represents the number of persons whose CD8 T cells recognize each individual HCMV-pp65 or IE1 peptide pool.
Figure 2.
Figure 2.
Greater diversity of HCMV-specific CD8+ T cell responses in HIV-positive subjects with controlled HCMV replication or recovering from AHCMV infection, compared with HIV-negative (HN) healthy individuals and patients who had uncontrolled HCMV replication. The number of distinct HCMV-pp65 and -IE1 pools of peptides detected by ELISPOT assay per individual. Each bar represents one individual; the number in bold type is the mean number of recognized pools per individual.
Figure 3.
Figure 3.
Magnitude of HCMV-specific CD8+ T cell responses. The number of pp65 and IE1-specific IFNγ-producing T cells identified for each subject in ELISPOT assays. Each bar represents one subject. The numbers in bold type are the mean numbers of specific T cells per subject.
Figure 4.
Figure 4.
Differentiation profiles of HCMV-specific CD8+ T cells. Flow-cytometry analysis of CD27 and CD28 coexpression gated on IFN-γ–producing CD8 T cells after stimulation with the dominant HCMV peptide pool as detected in the ELISPOT assay. Each display represents results from a representative donor from each group. Proportions of cells in each quadrant are represented in the labels.
Figure 5.
Figure 5.
Immune correlates of a stable recovery after AHCMV retinitis. A model based upon the experimental findings is proposed.
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