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CHARACTERIZATION OF CD8 T CELL HETEROGENEITY IN
CHRONIC HBV INFECTION BY FUNCTIONAL/PHENOTYPIC
PROFILING TO PREDICT THE EFFECT OF IMMUNE
MODULATION ON THE CD8 T CELL FUNCTION
Carolina Boni1, Marzia Rossi1,2, Andrea Vecchi1,2, Valeria
Barili1,2, Camilla Tiezzi1, Paola Fisicaro1,2, Ilaria Montali1,2,
Stephane Daffis3, Simon Fletcher3, Anuj Gaggar4, Alessandro
Loglio5, Arianna Alfieri1, Federica Brillo1, Diletta Laccabue1,2,
Marco Massari6, Chiara Boarini7, Gianluca Abbati7, Gabriele
Missale1,2, Pietro Lampertico8 and Carlo Ferrari1,2, (1)Unit of
Infectious Diseases and Hepatology, Azienda Ospedaliero-
Universitaria Di Parma, (2)Department of Medicine and
Surgery, University of Parma, (3)Gilead Sciences, Inc,
Foster City, USA, (4)Gilead Sciences, Inc., (5)Division
of Gastroenterology and Hepatology - CRC AM and a
Migliavacca” Center for Liver Diseases, Foundation Irccs Ca’
Granda Ospedale Maggiore Policlinico, Milan, Italy, (6)Unit
of Infectious Diseases, Azienda Usl- Irccs Di Reggio Emilia,
(7)Division of Internal Medicine 2, Azienda Ospedaliero-
Universitaria Di Modena, (8)Division of Gastroenterology and
Hepatology - CRC “a. M. and a. Migliavacca” Center for Liver
Disease, Foundation Irccs Ca’ Granda Ospedale Maggiore
Policlinico, Milan, Italy
Background: Exhausted CD8 T cells in chronic virus
infections are functionally heterogeneous and animal models
of infection show co-existence in individual infected hosts of
different T cell subsets with variable degrees of functionality
and response to checkpoint blockade The aim of this study
was to characterize the functional heterogeneity of HBV-specific
CD8 T cells in chronic HBV infection and to identify
CD8 T cell phenotypic profiles indicative of the overall level
of functional T cell impairment in individual patients and
predictive of response to immune modulatory strategies to
restore the T cell function Methods: We studied 26 HBeAg viremic
CHB patients, 12 CHB patients who achieved HBsAg
loss and anti-HBs seroconversion after NUC treatment, and
16 patients with spontaneous anti-HBs seroconversion after
chronic HBV carriage Subsets of exhausted dextramer
positive HBV-specific CD8 T cells were identified ex vivo
by co-expression of checkpoints/differentiation molecules
(PD1, CD127, BCL2, CXCR5, CD39, TIGIT), transcription
factors (TOX, TCF1, EOMES, Tbet) and cytokines (TNF-a
and IFN-g) Short-term T-cell lines were generated by 8-10
days PBMC stimulation with core and polymerase peptides
in the presence or absence of anti-oxidant and polyphenolic
compounds, PD-1/PD-L1 inhibitors and a selective agonist
of TLR-8 and tested for production of IFN-g, TNF-a and
CD107 degranulation Results: Initial analysis with PD-1 and
CD127 allowed to detect more exhausted PD1hiCD127low/-
HBV-specific CD8 cells only in chronic viremic patients
and conversely a large predominance of functionally more
efficient PD-1low/-CD127hi CD8 T cell subsets in resolved
patients. This more protective profile was also expressed
in a proportion of viremic CHB patients Importantly, these
patients responded more effectively to metabolic and immune
modulation in vitro The same accuracy of prediction of
individual patient responsiveness to in vitro modulation was
TOX and Bcl-2 Conclusion: The likelihood of response to
immune modulatory compounds can be predicted not only by
phenotypic profiling of HBV-specific but also of total CD8 T
cells, defining a composite bio-predictor easy to be used in
the daily clinical practice to identify potential responders to
immune modulation. |
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发表于 2020-10-31 17:12