TY - JOUR
T1 - Characterising EBV-associated lymphoproliferative diseases and the role of myeloid-derived suppressor cells
AU - Collins, Paul
AU - Fox, Christopher P.
AU - George, Lindsay C.
AU - Pearce, Hayden
AU - Ryan, Gordon Brendan
AU - De Santo, Carmela
AU - Mussai, Francis Jay
AU - Lewis, David
AU - Long, Heather M.
AU - Shannon-Lowe, Claire D.
PY - 2021/1/14
Y1 - 2021/1/14
N2 - Chronic active Epstein Barr virus (CAEBV) typically presents as persistent infectious mononucleosis-like disease and/or haemophagocytic lymphohistocytosis, reflecting ectopic EBV infection and lymphoproliferation of T and/or NK-cells. Clinical behaviour ranges from indolent, stable disease through to rapidly progressive, life-threatening disease. Whilst it is thought the chronicity and/or progression reflect an escape from immune control, very little is known about the phenotype and function of the infected cells versus co-resident non-infected population, nor about the mechanisms that could underpin their evasion of host immune surveillance. To investigate these questions, we developed a multicolour flow cytometry technique combining phenotypic and functional marker staining with in-situ hybridisation for the EBER RNAs expressed in every infected cell. This allows the identification, phenotyping and functional comparison of infected (EBERPOS) and non-infected (EBERNEG) lymphocyte subset(s) in patients' blood samples ex vivo. We have characterised CAEBV and HLH cases with monoclonal populations of discrete EBV-activated T-cell subsets, in some cases accompanied by EBV-activated NK-cell subsets, with longitudinal data on the infected cells' progression despite standard steroid-based therapy. Given that cytotoxic CD8+ T-cells with relevant EBV antigen specificity were detectable in the blood of the best studied patient, we searched for means whereby host surveillance might be impaired. This revealed a unique feature in almost every CAEBV patient studied: the presence of large numbers of myeloid derived suppressor cells which exhibited robust inhibition of T-cell growth. We suggest that their influence is likely to explain the host's failure to contain EBV-positive T/NK-cell proliferation.
AB - Chronic active Epstein Barr virus (CAEBV) typically presents as persistent infectious mononucleosis-like disease and/or haemophagocytic lymphohistocytosis, reflecting ectopic EBV infection and lymphoproliferation of T and/or NK-cells. Clinical behaviour ranges from indolent, stable disease through to rapidly progressive, life-threatening disease. Whilst it is thought the chronicity and/or progression reflect an escape from immune control, very little is known about the phenotype and function of the infected cells versus co-resident non-infected population, nor about the mechanisms that could underpin their evasion of host immune surveillance. To investigate these questions, we developed a multicolour flow cytometry technique combining phenotypic and functional marker staining with in-situ hybridisation for the EBER RNAs expressed in every infected cell. This allows the identification, phenotyping and functional comparison of infected (EBERPOS) and non-infected (EBERNEG) lymphocyte subset(s) in patients' blood samples ex vivo. We have characterised CAEBV and HLH cases with monoclonal populations of discrete EBV-activated T-cell subsets, in some cases accompanied by EBV-activated NK-cell subsets, with longitudinal data on the infected cells' progression despite standard steroid-based therapy. Given that cytotoxic CD8+ T-cells with relevant EBV antigen specificity were detectable in the blood of the best studied patient, we searched for means whereby host surveillance might be impaired. This revealed a unique feature in almost every CAEBV patient studied: the presence of large numbers of myeloid derived suppressor cells which exhibited robust inhibition of T-cell growth. We suggest that their influence is likely to explain the host's failure to contain EBV-positive T/NK-cell proliferation.
KW - Epstein-Barr Virus Infections
KW - Herpesvirus 4, Human
KW - Lymphoproliferative Disorders
KW - Myeloid-Derived Suppressor Cells
KW - antigens
KW - crossbreeding
KW - flow cytometry
KW - indolent
KW - infectious mononucleosis
KW - phenotype determination
UR - http://www.scopus.com/inward/record.url?scp=85099905447&partnerID=8YFLogxK
U2 - 10.1182/blood.2020005611
DO - 10.1182/blood.2020005611
M3 - Article
SN - 0006-4971
VL - 137
SP - 203
EP - 215
JO - Blood
JF - Blood
IS - 2
ER -