Cytomegalovirus (CMV) Epitope-Specific CD4 + T Cells Are Inflated in HIV + CMV + Subjects

• Published in: The Journal of immunology (1950) 2017-11, Vol.199 (9), p.3187-3201
• Main Authors: Abana, Chike O, Pilkinton, Mark A, Gaudieri, Silvana, Chopra, Abha, McDonnell, Wyatt J, Wanjalla, Celestine, Barnett, Louise, Gangula, Rama, Hager, Cindy, Jung, Dae K, Engelhardt, Brian G, Jagasia, Madan H, Klenerman, Paul, Phillips, Elizabeth J, Koelle, David M, Kalams, Spyros A, Mallal, Simon A
• Format: Article
• Language: English
• Subjects: ADP-ribosyl Cyclase 1 - immunology; Apoptosis; CD38 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; CD8 antigen; Complementarity-determining region 3; Cross-reactivity; CX3CR1 protein; Cytomegalovirus; Cytomegalovirus - immunology; Cytomegalovirus Infections - immunology; Cytomegalovirus Infections - pathology; Cytotoxicity; Drb1 protein; Effector cells; Endothelial cells; Epitopes; Epitopes, T-Lymphocyte - immunology; Female; Gag protein; Glycoprotein B; Granzyme B; Histocompatibility antigen HLA; HIV; HIV Infections - immunology; HIV Infections - pathology; HIV-1 - immunology; HLA-DR7 Antigen - immunology; Human immunodeficiency virus; Humans; Immunologic Memory; Immunological memory; Lymphocytes; Lymphocytes T; Male; Membrane Glycoproteins - immunology; Memory cells; T cell receptors; Tetanus; Transfection; Vaccines; Vascular diseases; Viral Proteins - immunology; Viremia
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1700851

Select CMV epitopes drive life-long CD8 T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4 T cells specific for human CMV (HCMV) are elevated in HIV HCMV subjects. To determine whether HCMV epitope-specific CD4 T cell memory inflation occurs during HIV infection, we used HLA-DR7 (DRB1*07:01) tetramers loaded with the glycoprotein B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4 T cells in coinfected HLA-DR7 long-term nonprogressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4 T cells were inflated among these HIV subjects compared with those from an HIV HCMV HLA-DR7 cohort or with HLA-DR7-restricted CD4 T cells from the HIV-coinfected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, EBV nuclear Ag 2, or HIV gag protein. Inflated DYS-specific CD4 T cells consisted of effector memory or effector memory-RA subsets with restricted TCRβ usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near-monoclonal TCR in a Jurkat cell-transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme B, CX CR1, CD38, or HLA-DR but less often coexpressed CD38 and HLA-DR The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4 T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease.