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J Immunol. 2017 Nov 1;199(9):3187-3201. doi: 10.4049/jimmunol.1700851. Epub 2017 Oct 2.

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

Author information

1
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232.
2
Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
3
School of Human Sciences, University of Western Australia, Perth, Western Australia 6009, Australia.
4
Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia 6150, Australia.
5
Stem Cell Transplantation, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
6
Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, United Kingdom; and.
7
Department of Medicine, Laboratory Medicine, and Global Health, University of Washington, Seattle, WA 98195.
8
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232; s.mallal@vanderbilt.edu.

Abstract

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, CX3CR1, 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.

PMID:
28972094
PMCID:
PMC5679304
DOI:
10.4049/jimmunol.1700851
[Indexed for MEDLINE]
Free PMC Article

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