CD4+CD28− T cell expansion in granulomatosis with polyangiitis (Wegener's) is driven by latent cytomegalovirus infection and is associated with an increased risk of infection and mortality

Abstract

Objective. Expanded populations of CD4؉ CD28؊ T cells with a cytotoxic phenotype have been repeatedly reported in patients with granulomatosis with polyangiitis (Wegener's) (GPA). In healthy individuals expansion of this T cell population follows cytomegalovirus (CMV) infection. We undertook this study to investigate whether CMV infection may be responsible for driving the expansion of CD4؉CD28؊ T cells in GPA patients and how this might relate to clinical features.Methods. Forty-eight GPA patients and 38 agematched healthy donors were included in the study. CMV-specific IgG in serum was detected by enzymelinked immunosorbent assay. Flow cytometric analysis was used to study T cell populations and phenotype. The presence of CMV in renal biopsy tissue from GPA patients was investigated by immunohistochemistry and polymerase chain reaction (PCR). Clinical information was obtained from patient records.Results. Populations of CD4؉CD28؊ T cells were only expanded in CMV-seropositive GPA patients and controls. In CMV-seropositive GPA patients we observed negative correlations between the percentages of CD4؉CD28؊ T cells and both the percentage of naive T cells and the glomerular filtration rate at presentation. There was a significant association between the percentage of CD4؉CD28؊ T cells and risk of infection and mortality. CMV could not be detected in renal tissue by PCR or immunohistochemistry. CMV seropositivity itself was not a risk factor for infection in a cohort of 182 patients with antineutrophil cytoplasmic antibody-associated vasculitis who had been recruited into clinical trials performed by the European Vasculitis Study Group.Conclusion. The expansion of CD4؉CD28؊ T cells in GPA patients is associated with CMV infection and leads to a reduction in the number of naive T cells in peripheral blood. Patients with expanded CD4؉CD28؊ T cells have significantly increased mortality and risk of infection.

Cytomegalovirus-Associated CD4+CD28null Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction

“…Although sampling was not continued beyond the first year, the intensive protocol and detailed phenotyping conducted during this critical period add robustness and relevance to these findings, which are novel to transplantation but resonate with the inverse association between circulating CD4 + CD28 null cells and renal function in a cross-sectional study of stable patients with renal vasculitis (6). This link between CMV, inflammation (discussed earlier) cytotoxic CD4 + CD28 null cell expansion, endothelial injury, and allograft dysfunction may contribute to explaining the well-recognized but incompletely understood association between inflammation and graft outcome (30,31) and may even go toward explaining the "transplant paradox" by which improvements in acute rejection rates have not been mirrored by long-term improvement in graft survival (32).…”

“…CMV prophylaxis with 100 days of valganciclovir was given to the D+RÀ serostatus group only, with dose adjustment for renal function. Serial whole blood samples were taken for CMV DNA polymerase chain reaction in all patients at day 0 (before transplantation) and then at weeks 1,2,3,4,6,8,10,12,16,20,24,28,34,40,46, and 52. The clinical team remained unaware of these results, and no changes in clinical management ensued (it is not unit policy to undertake viral load testing and preemptive therapy in the context of asymptomatic CMV infection, as is the case in most centers, so these assessments were undertaken for research purposes only).…”

Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity

“…6 The decreased lymphopoiesis and thymic involution also result in a reduction of naïve T cells and increasing frequency of memory T cells, 10,11 such as antigen-experienced memory T cells that respond to low-threshold stimuli and secrete cytotoxic factors, such as perforin and granzyme B (GrB). 12,13 For example, the elderly accumulate highly differentiated CD8 1 CD28 Low/-T cells 10,14 expressing GrB, 15 although a similar type of potentially cytotoxic cells are also induced after cytomegalovirus (CMV) and HIV infections (see Strioga et al 16 ); in some autoimmune diseases such as rheumatoid arthritis (RA), Graves disease, multiple sclerosis (MS), type 1 diabetes (T1D), and Wegener's granulomatosis [17][18][19] ; and in patients with inflammatory breast cancer after high-dose chemotherapy followed with autologous progenitor cell transplantation (auto-HSCT). 20 We recently found that antitumor effector GrB 1 CD8 1 T cells can also be induced when tumorsupporting regulatory B cells (Bregs) are rendered into activators expressing 4-1BBL.…”

Cytomegalovirus as a Driver of Excess Cardiovascular Mortality in Rheumatoid Arthritis

“…[4][5][6][7] Expansions of CD4 + CD28 − T-cells reported in RA and other autoimune diseases frequently exceed 5-10% (when not stratified by CMV infection status) and so vastly exceed the percentages observed in CMV − individuals where reported (about 1-2% in the literature). A small number of studies in RA and granulomatosis with polyangiitis (GPA) were actually stratified by CMV serology and found that the CD4 + CD28 − T-cell subset was increased by 10 to 20-fold in the CMV + population.…”

“…A small number of studies in RA and granulomatosis with polyangiitis (GPA) were actually stratified by CMV serology and found that the CD4 + CD28 − T-cell subset was increased by 10 to 20-fold in the CMV + population. 4,6,7 It is becoming increasingly obvious that the expansions of CD4 + CD28 − T-cells observed in RA are explained by the CMV + population of RA patients; they may also explain the increased incidence of CV morbidity and mortality. This is, because, to make things worse, CMV infection in RA produces larger expansions of these cells than in otherwise healthy people, suggesting RA itself might accelerate these expansions.…”