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

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 tetramers loaded with the glycoprotein-B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4+ T cells in co-infected, HLA-DR7+ long-term non-progressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4+ T cells were inflated among these HIV+ subjects compared to those from a HIV− HCMV+ HLA-DR7+ cohort, or to HLA-DR7-restricted CD4+ T cells from the HIV co-infected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, Epstein-Barr virus nuclear antigen 2 or HIV gag protein. Inflated DYS-specific CD4+ T cells comprised effector memory or effector memory-RA+ subsets with restricted TCR-beta 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 were less often CD38+HLA-DR+ co-expressing. 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.

Dengue-specific CD8+ T cell subsets display specialized transcriptomic and TCR profiles

“…Our analysis of TRB repertoire overlap between CD8 + T cell subsets reveals that DENV-specific CD8 + Tem and Temra cells have the highest degree of overlap. Thus, it is possible that some DENV-specific Tem and Temra cells may share certain CDR3 sequences as previously observed for HCMV-specific CD4 + Tem and Temra cells (50). Since Temra cells also have a more specialized gene expression profile, we speculate that some Temra cells may derive from Tem cell clones and then undergo clonal expansion and differentiation.…”

Deciphering targets of Th17 cells fate: From metabolism to nuclear receptors

“…In the context of antiviral immune responses, GzmB‐derived CD4 + CD28‐ T lymphocytes were demonstrated in patients after citomegalovirus (CMV) infection . Similar features were observed in patients with HIV, and increased GzmB‐derived cells from stimulated Th1 and Th17 lymphocytes were thought to be associated with diverse tissue damage during infection course . Also, during Dengue virus (DENV) infection, CXCR1 + Eomes + T‐bet + GzmB + perforin + CD45RA + CD4 + T lymphocytes were described with cytotoxic function .…”

“…41 Similar features were observed in patients with HIV, and increased GzmB-derived cells from stimulated Th1 and Th17 lymphocytes were thought to be associated with diverse tissue damage during infection course. 42,43 Also, during Dengue virus (DENV) infection, CXCR1 + Eomes + T-bet + GzmB + perforin + CD45RA + CD4 + T lymphocytes were described with cytotoxic function. 8 These reinforce the diverse and differentiated phenotype of CTL CD4 T lymphocytes, which can include naïve to memory cells.…”

The impact of inflationary cytomegalovirus‐specific memory T cells on anti‐tumour immune responses in patients with cancer

“…We now have a better picture of how the unique immunological memory inflation driven by CMV is initiated and controlled, as well as its association with age, sex and environmental factors. Although not common, inflationary CMV pp65‐specific CD4 + T cells that can express granzyme B from HIV‐positive/CMV‐positive individuals have also been described, thus expanding the immune repertoire of inflationary responses to CMV infection as well as their role in mediating immunopathology. Targeting CMV could potentially represent a biologically viable immunomodulator; harnessing clinically relevant immune responses may, therefore, pave the way for developing cutting‐edge immunotherapies for patients with malignancies (for a summary of ongoing clinical trials see Table ).…”