ABSTRACT
Early human herpesvirus 6 (HHV6) reactivation after hematopoietic stem cell transplantation (HSCT) is associated with poor survival. We characterized HHV6 immuneresponses in HSCT patients during lymphopenia. Prospectively, HHV6 DNA-load was measured weekly by realtime-PCR. Numbers of IFNγ-producing HHV6-T-cells were retrospectively determined by enzyme-linked immunospot assay 2 months after HSCT. HHV6-specific T-cell proliferative capacity was analyzed with a newly developed assay using antigen-presenting autologous HHV6-infected PBMC. Fifty-six patients were included (median age 4.6 years; range 0.2-21.2 years). HHV6-reactivation occurred in 29/56 (52%) patients with a median time of 14 (range 1-41) days after HSCT. The median number of IFN-γ producing HHV6-specific T-cells at 2 months and the HHV6-specific CD8+ T-cell proliferative capacity at 6 months after HSCT was increased after HHV6-reactivation compared to non-reactivating patients (P=0.006 and p=0.019). In conclusion, HHV6-specific immuneresponses can be initiated during lymphopenia early after HSCT, which implicates a potential window for development of HHV6-specific (immuno)therapy.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Herpesvirus 6, Human/immunology , Roseolovirus Infections/immunology , Roseolovirus Infections/virology , Stem Cells/immunology , Adolescent , Adult , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/virology , CD8-Positive T-Lymphocytes/virology , Cell Proliferation , Child , Child, Preschool , Cohort Studies , DNA, Viral/genetics , DNA, Viral/immunology , Female , Hematopoietic Stem Cell Transplantation/methods , Herpesvirus 6, Human/genetics , Humans , Infant , Interferon-gamma/immunology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/virology , Lymphopenia/immunology , Lymphopenia/virology , Male , Prospective Studies , Retrospective Studies , Roseolovirus Infections/genetics , Virus Activation/genetics , Virus Activation/immunology , Young AdultABSTRACT
Several T cell abnormalities have been described in common variable immunodeficiency (CVID), a B cell disorder of mainly unknown origin. A subset of CVID patients suffers from frequent reactivations of herpes viruses. We studied T cell function in CVID [and in a subset of paediatric patients with specific antibody deficiency (SAD)] by measuring T cell proliferation and cytokine production in response to herpes virus-antigens in paediatric CVID patients (n=9) and paediatric SAD patients (n=5), in adult CVID patients (n=14) and in healthy controls. Paediatric CVID patients, but not SAD patients, displayed moderately increased CD8+ T cell proliferation in response to cytomegalovirus, human herpes virus type 6B (HHV6-B) and herpes simplex virus compared to controls. CD8+ T cell responses in adult CVID patients tended to be increased in response to cytomegalovirus and herpes simplex virus. In response to stimulation with herpes virus antigens, the proinflammatory cytokines interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF)-alpha and interferon inducible protein (IP)-10 were produced. Overall, no major differences were detected in cytokine production upon stimulation between patients and controls, although higher IL-10 and IL-12 production was detected in paediatric patients. In conclusion, cellular immunity against herpes virus antigens appears undisturbed in CVID patients, although defects in subpopulations of CVID patients cannot be excluded.
Subject(s)
Adenoviruses, Human/immunology , Antigens, Viral/immunology , Common Variable Immunodeficiency/immunology , Herpesviridae/immunology , IgG Deficiency/immunology , T-Lymphocyte Subsets/immunology , Adenoviruses, Human/physiology , Adolescent , Adult , Chemokine CXCL10/biosynthesis , Chemokine CXCL10/genetics , Chemokine CXCL10/metabolism , Child , Child, Preschool , Female , Gastrointestinal Diseases/etiology , Herpesviridae/physiology , Humans , Immunity, Cellular , Interleukins/biosynthesis , Interleukins/genetics , Interleukins/metabolism , Lymphocyte Activation/immunology , Male , Middle Aged , Recurrence , Respiratory Tract Infections/etiology , Respiratory Tract Infections/virology , T-Lymphocyte Subsets/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Virus ActivationABSTRACT
We studied simultaneously Epstein-Barr virus (EBV)-specific CD4(+) and CD8(+) T cell responses during and after infectious mononucleosis (IM), using a previously described 12-day stimulation protocol with EBNA1 or BZLF1 peptide pools. Effector function of EBV-specific T cells was determined after restimulation by measuring intracellular interferon-gamma production. During IM, BZLF1-specifc CD4(+) T cell responses were dominant compared with CD8(+) T cell responses. EBNA1-specific CD4(+) and CD8(+) T cell responses were low and remained similar for 6 months. However, 6 months after IM, BZLF1-specific CD4(+) T cell responses had declined, but CD8(+) T cell responses had increased. At diagnosis, EBV-specific CD8(+) T cells as studied by human leucocyte antigen class I tetramer staining comprised a tetramer(bright)CD8(bright) population consisting mainly of CD27(+) memory T cells and a tetramer(dim)CD8(dim) population consisting primarily of CD27(-) effector T cells. The remaining EBV-specific CD8(+) T cell population 6 months after the diagnosis of IM consisted mainly of tetramer(bright)CD8(bright) CD27(+) T cells, suggesting preferential preservation of memory T cells after contraction of the EBV-specific T cell pool.
