PMID- 34512670
OWN - NLM
STAT- MEDLINE
DCOM- 20211223
LR  - 20211223
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 12
DP  - 2021
TI  - Follicular Helper T (T(FH)) Cell Targeting by TLR8 Signaling For Improving 
      HBsAg-Specific B Cell Response In Chronic Hepatitis B Patients.
PG  - 735913
LID - 10.3389/fimmu.2021.735913 [doi]
LID - 735913
AB  - Identifying signaling pathways that induce B cell response can aid functional 
      cure strategies for chronic hepatitis B infection (CHB). TLR8 activation with 
      ssRNA was shown to enhance follicular helper T cell (T(FH)) function leading to 
      improved B cell responses in vitro. We investigated whether this mechanism can 
      rescue an exhausted immune response in CHB infection. Effect of TLR8 agonism on 
      supporting cytokines and T(FH) and B cells were evaluated using ex vivo and in 
      vitro assays. The ability of an oral TLR8 agonist to promote T(FH) and B cell 
      response was tested in samples from phase 1b clinical trial. TLR8 agonism induced 
      T(FH) polarizing cytokine IL-12 in monocytes. Treatment of peripheral blood 
      mononuclear cells (PBMCs) from CHB patients with TLR8 agonists induced cytokine 
      IL-21 by T(FH) cells with enhanced IL-21(+)BCL-6(+) and ICOS(+)BCL-6(+) 
      co-expression. Mechanistically, incubation of isolated naive CD4(+) T cells with 
      TLR8 triggered monocytes resulted in their differentiation into 
      IL-21(+)ICOS(+)BCL-6(+) T(FH) in an IL-12 dependent manner. Furthermore, 
      co-culture of these IL-21 producing T(FH) with autologous naive B cells led to 
      enhanced memory (CD19(+)CD27(+)) and plasma B cell generation 
      (CD19(+)CD27(++)CD38(+)) and IgG production. Importantly, in T(FH) from CHB 
      patients treated with an oral TLR8 agonist, HBsAg-specific BCL-6, ICOS, IL-21 and 
      CD40L expression and rescue of defective activation induced marker (AIM) response 
      along with partial restoration of HBsAg-specific B cell ELISPOT response was 
      evident. TLR8 agonism can thus enhance HBV-specific B cell responses in CHB 
      patients by improving monocyte-mediated T(FH) function and may play a role in 
      achieving HBV functional cure.
CI  - Copyright (c) 2021 Ayithan, Tang, Tan, Chen, Wallin, Fletcher, Kottilil and Poonia.
FAU - Ayithan, Natarajan
AU  - Ayithan N
AD  - Division of Clinical Care and Research, Institute of Human Virology, University 
      of Maryland School of Medicine, Baltimore, MD, United States.
FAU - Tang, Lydia
AU  - Tang L
AD  - Division of Clinical Care and Research, Institute of Human Virology, University 
      of Maryland School of Medicine, Baltimore, MD, United States.
FAU - Tan, Susanna K
AU  - Tan SK
AD  - Clinical Research, Gilead Sciences Inc., Foster City, CA, United States.
FAU - Chen, Diana
AU  - Chen D
AD  - Clinical Research, Gilead Sciences Inc., Foster City, CA, United States.
FAU - Wallin, Jeffrey J
AU  - Wallin JJ
AD  - Clinical Research, Gilead Sciences Inc., Foster City, CA, United States.
FAU - Fletcher, Simon P
AU  - Fletcher SP
AD  - Clinical Research, Gilead Sciences Inc., Foster City, CA, United States.
FAU - Kottilil, Shyam
AU  - Kottilil S
AD  - Division of Clinical Care and Research, Institute of Human Virology, University 
      of Maryland School of Medicine, Baltimore, MD, United States.
FAU - Poonia, Bhawna
AU  - Poonia B
AD  - Division of Clinical Care and Research, Institute of Human Virology, University 
      of Maryland School of Medicine, Baltimore, MD, United States.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210826
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Antiviral Agents)
RN  - 0 (BCL6 protein, human)
RN  - 0 (Hepatitis B Surface Antigens)
RN  - 0 (Hexanols)
RN  - 0 (ICOS protein, human)
RN  - 0 (Inducible T-Cell Co-Stimulator Protein)
RN  - 0 (Interleukins)
RN  - 0 (Proto-Oncogene Proteins c-bcl-6)
RN  - 0 (Pyrimidines)
RN  - 0 (TLR8 protein, human)
RN  - 0 (Toll-Like Receptor 8)
RN  - 147205-72-9 (CD40 Ligand)
RN  - MKM3CA6LT1 (interleukin-21)
RN  - RM4GJT3SMQ (selgantolimod)
SB  - IM
MH  - Antiviral Agents/*therapeutic use
MH  - B-Lymphocytes/*drug effects/immunology/metabolism/virology
MH  - CD40 Ligand/metabolism
MH  - Case-Control Studies
MH  - Cells, Cultured
MH  - Enzyme-Linked Immunospot Assay
MH  - Hepatitis B Surface Antigens/*immunology
MH  - Hepatitis B virus/*immunology/pathogenicity
MH  - Hepatitis B, Chronic/*drug therapy/immunology/metabolism/virology
MH  - Hexanols/*therapeutic use
MH  - Host-Pathogen Interactions
MH  - Humans
MH  - Inducible T-Cell Co-Stimulator Protein/metabolism
MH  - Interleukins/metabolism
MH  - Proto-Oncogene Proteins c-bcl-6/metabolism
MH  - Pyrimidines/*therapeutic use
MH  - Signal Transduction
MH  - T Follicular Helper Cells/*drug effects/immunology/metabolism/virology
MH  - Toll-Like Receptor 8/*agonists/metabolism
MH  - Treatment Outcome
PMC - PMC8428528
OTO - NOTNLM
OT  - B cell
OT  - HBsAg-specific B cell response
OT  - activation induced marker (AIM)
OT  - chronic hepatitis B
OT  - follicular helper T cell
OT  - inflammatory cytokine
OT  - selgantolimod (SLGN)
OT  - toll-like receptor 8
COIS- SKT, DC, JJW and SPF were employed by Gilead Sciences Inc. BP received financial 
      support paid to University of Maryland from Gilead Sciences. The authors also 
      declare that this study received funding from Gilead Sciences. The funder had the 
      following involvement with the study: interpretation of data/editing of 
      manuscript.
EDAT- 2021/09/14 06:00
MHDA- 2021/12/24 06:00
PMCR- 2021/01/01
CRDT- 2021/09/13 06:44
PHST- 2021/07/03 00:00 [received]
PHST- 2021/08/11 00:00 [accepted]
PHST- 2021/09/13 06:44 [entrez]
PHST- 2021/09/14 06:00 [pubmed]
PHST- 2021/12/24 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2021.735913 [doi]
PST - epublish
SO  - Front Immunol. 2021 Aug 26;12:735913. doi: 10.3389/fimmu.2021.735913. eCollection 
      2021.