Prof Pierre Delobel

Universities and Institutes of France

France

October 1, 2022

Description

  • Organisation/Company: INSERM
  • Research Field: Biological sciences › Biology
  • Researcher Profile: Recognised Researcher (R2)
  • Application Deadline: 01/10/2022 21:00 - Europe/Athens
  • Location: France › Toulouse
  • Type Of Contract: Permanent
  • Job Status: Full-time
  • Hours Per Week: 40
  • Offer Starting Date: 01/11/2022
  • Phenotype, functional properties, and gut recruitment of CX3CR1+ effector lymphocytes in HIV-1-infected individuals on antiretroviral therapy

    Research unit: Toulouse Institute for Infectious and Inflammatory Diseases – Infinity INSERM UMR1291- CNRS UMR5051 – Toulouse III University

    Team Viral Infections : persistence, host response, and pathophysiology

    Specialty : Immunology

    Scientific project manager: Prof. Pierre DELOBEL, MD, PhD

    Key words:

    HIV-1, lymphocytes, CX3CR1, CX3CL1, gut

    Project summary

    The gut is a key organ for HIV replication and persistence on antiretroviral therapy. Despite effective treatment, the gut immune barrier remains incompletely restored in HIV-1-infected individuals. This leaky barrier is responsible for chronic microbial translocation from the gut lumen into the bloodstream, and subsequent chronic inflammation. A vicious circle between chronic mucosal inflammation and defective immune reconstitution could be induced by antigenic stimuli from cells harboring HIV proviruses and/or from microbial products, and persistent dysregulation of immune cells recruitment to the gut mucosa. In treated HIV-1-infected individuals, the Tb7/Treg ratio remains imbalanced, while Tb and effector memory CD8+ T cells are efficiently recruited in the gut mucosa.

    The CX3CL1-CX3CR1 chemotactic axis is involved in the recruitment of terminally differentiated effector lymphocytes among CD8+T cells, gd T cells, and NK cells that share CX3CR1 expression. CX3CR1 ligand, the CX3CL1 chemokine, is produced by epithelial and endothelial in the gut mucosa. CX3CR1+ effector lymphocytes could have retained cytotoxic properties without being fully exhausted and could thus play a key role in antiviral response in tissues.

    We plan to perform in depth characterization of CX3CR1+ effector lymphocytes, as well as CX3CL1 expression, from blood and gut samples already collected in the ANRS EP61 GALT study. This study had recruited 42 HIV-1-infected individuals on antiretroviral therapy, and 42 uninfected controls, for whom duodenal, ileal, and colonic biopsies have been collected, in parallel to blood samples. CX3CR1+ CD8+ T cells, gd T cells, and NK cells will be characterized in blood and gut samples regarding their phenotype and function. CX3CL1 production in the gut mucosa will also be studied, notably the mechanisms regulating CX3CL1 expression using ex-vivo models of gut histocultures and primary enterocytes cultures.

    This study will allow in depth characterization of the phenotype and functional properties of effector CX3CR1+ CD8+ T cells, gd T cells, and NK cells, and information on the effectiveness of the CX3CL1-CX3CR1 axis for immune cells recruitment to the gut in the setting of HIV-1 infection.

    References

  • Imai, T. et al. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 91, 521-530 (1997).
  • Foussat, A. et al. Fractalkine receptor expression by T lymphocyte subpopulations and in vivo production of fractalkine in human. Eur J Immunol 30, 87-97 (2000).
  • Combadiere, B., et al. The chemokine receptor CX3CR1 controls homing and anti-viral potencies of CD8 effector-memory T lymphocytes in HIV-infected patients. AIDS 17, 1279-1290 (2003).
  • Hudson, W. H. et al. Proliferating Transitory T Cells with an Effector- like Transcriptional Signature Emerge from PD-1(+) Stem-like CD8(+) T Cells during Chronic Infection. Immunity 51, 1043-1058 e1044 (2019).
  • Gordon, C. L. et al. Induction and Maintenance of CX3CR1-Intermediate Peripheral Memory CD8(+) T Cells by Persistent Viruses and Vaccines. Cell Rep 23, 768-782 (2018).
  • Gerlach, C. et al. The Chemokine Receptor CX3CR1 Defines Three Antigen- Experienced CD8 T Cell Subsets with Distinct Roles in Immune Surveillance and Homeostasis. Immunity 45, 1270-1284 (2016).
  • Yamauchi, T. et al. T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors. Nature communications 12, 1402 (2021).
  • Yan, Y. et al. CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy. JCI insight 3 (2018).
  • Previous work on this topic:

  • Mavigner, M. et al. Altered CD4+ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals. J Clin Invest122, 62-69 (2012).
  • Loiseau, C. et al. CCR6(-) regulatory T cells blunt the restoration of gut Tb7 cells along the CCR6-CCL20 axis in treated HIV-1-infected individuals. Mucosal Immunol 9, 1137-1150 (2016).
  • Loiseau, C. et al. Increase of CXCR3+ T cells impairs Tb7 cells recruitment in the small intestine mucosa through IFN-gamma and IL-18 during treated HIV-1 infection. J Infect Dis (2019).
  • Nayrac, M. et al. Tb2 cells are efficiently recruited in the gut by CCL28 as an alternative to CCL20 but do not compensate for the loss of Tb7 cells in treated HIV-1-infected individuals. Mucosal Immunol 14, 219-228 (2021).
  • Required Research Experiences
  • RESEARCH FIELD
  • Biological sciences › Biology

  • YEARS OF RESEARCH EXPERIENCE
  • 1 - 4

    Offer Requirements
  • REQUIRED EDUCATION LEVEL
  • Biological sciences: PhD or equivalent

  • REQUIRED LANGUAGES
  • FRENCH: Good

    Skills/Qualifications

    Mutliparametric flow cytometry (BD Symphony)

    Cell sorting

    Molecular biology (qPCR, NGS, RNAseq)

    Cell culture

    Virus culture in BSL3 environment

    Specific Requirements

    Knowledge in immuno-virology / HIV infection

    Contact Information
  • Organisation/Company: INSERM
  • Department: U1291 - Toulouse Institute for Infectious and Inflammatory Diseases (Infinity)
  • Organisation Type: Higher Education Institute
  • Website: https: // www. infinity.inserm.fr
  • Country: France
  • City: Toulouse
  • Postal Code: 31024
  • Street: 1 place, docteur Baylac
  • Similar Jobs

    Add to favorites Read more...

    Postdoctal Position On Bioelectricity Topographic-Sensing

    Research Field: Biological sciences the team of Dr. Wang Xi at Institut Jacques Monod (IJM) are hiring bioelectrical and 3D topographic signals on cell and organ differentiation, migration, proliferation and metabolism. electrical signals stemming from...

    Add to favorites Read more...

    Post-Doc In Oncology

    Offer: the Laboratory of Dr. Vincent Goffin at INEM (Institut Necker Enfants Keywords: prostate cancer, CRPC, resistance to treatment, stem/progenitor cells, cell plasticity, therapeutic targeting, organoids, mouse models, human The project builds on solid data...