PMID- 36150362
OWN - NLM
STAT- MEDLINE
DCOM- 20221018
LR  - 20221018
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 84
DP  - 2022 Oct
TI  - Immune checkpoint expression on HIV-specific CD4+ T cells and response to their 
      blockade are dependent on lineage and function.
PG  - 104254
LID - S2352-3964(22)00436-4 [pii]
LID - 10.1016/j.ebiom.2022.104254 [doi]
LID - 104254
AB  - BACKGROUND: Immune checkpoint blockade (ICB) partially reverses the dysfunctional 
      state of antigen-specific T cell in chronic infections. However, its impact on 
      the diverse subsets of CD4+ T cells in humans is largely unknown. METHODS: We 
      examined immune checkpoint (IC) expression and function in HIV-specific CD4+ T 
      cells of viremic individuals (>/=5000 vRNA cp/ml, n = 17) prior to ART and persons 
      with spontaneous (n = 11) or therapy-induced (n = 16) viral suppression (<40 
      cp/ml). We investigated IC patterns associated with exhaustion-related 
      transcription factors and chemokine receptors using activation-induced marker 
      assays. We determined effector functions representative of T(FH), T(H)1, and 
      T(H)17/T(H)22 using RNA flow cytometric fluorescence in situ hybridization 
      (FISH). We compared increase in cytokine expression upon ICB across functions and 
      patient status. FINDINGS: Expression of dysfunction-related molecules, such as 
      transcription factors and ICs PD-1, TIGIT, and CD200, followed a hierarchy 
      associated with infection status and effector profile. In vitro responsiveness to 
      PD-L1 blockade varied with defined functions rather than IC levels: frequencies 
      of cells with T(H)1- and T(H)17/T(H)22-, but not T(FH)-related functions, 
      increased. Cells co-expressing T(H)1 and T(FH) functions showed response to ICB, 
      suggesting that the cell's state rather than function dictates responsiveness to 
      PD-L1 blockade. Response to PD-L1 blockade was strongest in viremic participants 
      and reduced after ART initiation. INTERPRETATION: Our data highlight a 
      polarization-specific regulation of IC expression and differing sensitivities of 
      antigen-specific T helper subsets to PD-1-mediated inhibition. This heterogeneity 
      may direct and constrain ICB efficacy in restoring CD4+ T cell function in HIV 
      infection and other diseases. FUNDING: NIH, CIHR, CFI, FRQS.
CI  - Copyright (c) 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
FAU - Brunet-Ratnasingham, Elsa
AU  - Brunet-Ratnasingham E
AD  - Research Centre of the Centre Hospitalier de l'Universite de Montreal (CRCHUM), 
      Montreal, Quebec, Canada; Universite de Montreal, Montreal, Quebec, Canada.
FAU - Morou, Antigoni
AU  - Morou A
AD  - Research Centre of the Centre Hospitalier de l'Universite de Montreal (CRCHUM), 
      Montreal, Quebec, Canada; Universite de Montreal, Montreal, Quebec, Canada.
FAU - Dube, Mathieu
AU  - Dube M
AD  - Research Centre of the Centre Hospitalier de l'Universite de Montreal (CRCHUM), 
      Montreal, Quebec, Canada.
FAU - Niessl, Julia
AU  - Niessl J
AD  - Research Centre of the Centre Hospitalier de l'Universite de Montreal (CRCHUM), 
      Montreal, Quebec, Canada; Universite de Montreal, Montreal, Quebec, Canada.
FAU - Baxter, Amy E
AU  - Baxter AE
AD  - Research Centre of the Centre Hospitalier de l'Universite de Montreal (CRCHUM), 
      Montreal, Quebec, Canada; Universite de Montreal, Montreal, Quebec, Canada.
FAU - Tastet, Olivier
AU  - Tastet O
AD  - Research Centre of the Centre Hospitalier de l'Universite de Montreal (CRCHUM), 
      Montreal, Quebec, Canada.
FAU - Brassard, Nathalie
AU  - Brassard N
AD  - Research Centre of the Centre Hospitalier de l'Universite de Montreal (CRCHUM), 
      Montreal, Quebec, Canada.
FAU - Ortega-Delgado, Gloria
AU  - Ortega-Delgado G
AD  - Research Centre of the Centre Hospitalier de l'Universite de Montreal (CRCHUM), 
      Montreal, Quebec, Canada.
FAU - Charlebois, Roxanne
AU  - Charlebois R
AD  - Research Centre of the Centre Hospitalier de l'Universite de Montreal (CRCHUM), 
      Montreal, Quebec, Canada.
FAU - Freeman, Gordon J
AU  - Freeman GJ
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, USA.
FAU - Tremblay, Cecile
AU  - Tremblay C
AD  - Research Centre of the Centre Hospitalier de l'Universite de Montreal (CRCHUM), 
      Montreal, Quebec, Canada; Universite de Montreal, Montreal, Quebec, Canada.
FAU - Routy, Jean-Pierre
AU  - Routy JP
AD  - Chronic Viral Illnesses Service and Division of Hematology, McGill University 
      Health Centre, Montreal, Quebec, Canada.
FAU - Kaufmann, Daniel E
AU  - Kaufmann DE
AD  - Research Centre of the Centre Hospitalier de l'Universite de Montreal (CRCHUM), 
      Montreal, Quebec, Canada; Universite de Montreal, Montreal, Quebec, Canada. 
      Electronic address: daniel.kaufmann@umontreal.ca.
LA  - eng
GR  - P01 AI056299/AI/NIAID NIH HHS/United States
GR  - R01 HL092565/HL/NHLBI NIH HHS/United States
GR  - R37 AI112787/AI/NIAID NIH HHS/United States
PT  - Journal Article
DEP - 20220920
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - 0 (B7-H1 Antigen)
RN  - 0 (Cytokines)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 0 (Receptors, Chemokine)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (Transcription Factors)
RN  - 63231-63-0 (RNA)
SB  - IM
MH  - *B7-H1 Antigen/metabolism
MH  - CD4-Positive T-Lymphocytes
MH  - Cytokines/metabolism
MH  - *HIV Infections
MH  - Humans
MH  - Immune Checkpoint Inhibitors
MH  - In Situ Hybridization, Fluorescence
MH  - Programmed Cell Death 1 Receptor/genetics/metabolism
MH  - RNA/therapeutic use
MH  - Receptors, Chemokine/metabolism/therapeutic use
MH  - Receptors, Immunologic/metabolism
MH  - Transcription Factors/metabolism
PMC - PMC9508408
OTO - NOTNLM
OT  - CD4+ T cell subsets
OT  - HIV-specific CD4+ T cells
OT  - Immune checkpoint blockade
OT  - PD-1
OT  - T cell dysfunction
OT  - TOX
COIS- Declaration of interests G.J.F. has patents/pending royalties on the PD-1/PD-L1 
      pathway from Roche, Merck M.S.D., Bristol-Myers-Squibb, Merck K.G.A., 
      Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, and Novartis. G.J.F. 
      has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, 
      Triursus, iTeos, and NextPoint. GJF has equity in Nextpoint, Triursus, and Xios. 
      The anti-PD-L1 antibody BMS-936559 and the anti-TIGIT antibody BMS-g86207-Ab were 
      given by Bristol-Myers Squibb. C.T. serves as a consultant and has received 
      honoraria from Merck, Gilead, G.S.K., AstraZeneca and Medicago. None of 
      aforementioned companies had implications in the design and interpretation of the 
      experiments performed in this manuscript.
EDAT- 2022/09/24 06:00
MHDA- 2022/10/19 06:00
PMCR- 2022/09/20
CRDT- 2022/09/23 18:26
PHST- 2021/09/08 00:00 [received]
PHST- 2022/08/18 00:00 [revised]
PHST- 2022/08/26 00:00 [accepted]
PHST- 2022/09/24 06:00 [pubmed]
PHST- 2022/10/19 06:00 [medline]
PHST- 2022/09/23 18:26 [entrez]
PHST- 2022/09/20 00:00 [pmc-release]
AID - S2352-3964(22)00436-4 [pii]
AID - 104254 [pii]
AID - 10.1016/j.ebiom.2022.104254 [doi]
PST - ppublish
SO  - EBioMedicine. 2022 Oct;84:104254. doi: 10.1016/j.ebiom.2022.104254. Epub 2022 Sep 
      20.