CCR6(-) regulatory T cells blunt the restoration of gut Th17 cells along the CCR6-CCL20 axis in treated HIV-1-infected individuals

C Loiseau; M Requena; M Mavigner; M Cazabat; N Carrere; B Suc; K Barange; L Alric; B Marchou; P Massip; J Izopet; P Delobel

doi:10.1038/mi.2016.7

CCR6(-) regulatory T cells blunt the restoration of gut Th17 cells along the CCR6-CCL20 axis in treated HIV-1-infected individuals

Mucosal Immunol. 2016 Sep;9(5):1137-50. doi: 10.1038/mi.2016.7. Epub 2016 Feb 17.

Authors

C Loiseau¹, M Requena², M Mavigner³, M Cazabat^{1

2}, N Carrere^{4

5}, B Suc^{4

5}, K Barange⁶, L Alric^{4

7

8}, B Marchou^{4

9}, P Massip^{4

9}, J Izopet^{1

2

4}, P Delobel^{1

4

9}

Affiliations

¹ INSERM, UMR1043, Toulouse, France.
² CHU de Toulouse, Laboratoire de Virologie, Toulouse, France.
³ Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
⁴ Université Toulouse III Paul Sabatier, Toulouse, France.
⁵ CHU de Toulouse, Service de Chirurgie Générale et Digestive, Toulouse, France.
⁶ CHU de Toulouse, Service de Gastro-Entérologie et Hépatologie-Pôle Digestif, Toulouse, France.
⁷ CHU de Toulouse, Service de Médecine Interne-Pôle Digestif, Toulouse, France.
⁸ IRD UMR152, Toulouse, France.
⁹ CHU de Toulouse, Service des Maladies Infectieuses et Tropicales, Toulouse, France.

PMID: 26883727
DOI: 10.1038/mi.2016.7

Abstract

The gut CD4(+) T cells, particularly the T helper type 17 (Th17) subset, are not completely restored in most HIV-1-infected individuals despite combined antiretroviral therapy, when initiated at the chronic phase of infection. We show here that the CCR6-CCL20 chemotactic axis is altered, with reduced CCL20 production by small intestine epithelial cells in treated HIV-1-infected individuals. This leads to impaired CCR6(+)CD4(+) T-cell homing, particularly Th17 cells, to the small intestine mucosa. In contrast, the frequency of gut FoxP3(+) T regulatory (Treg) cells, specifically the CCR6(-) subset, was increased. The resulting imbalance in the Th17/CCR6(-) Treg ratio and the associated shift from interleukin (IL)-17 to IL-10 and transforming growth factor-β (TGF-β) blunts CCL20 production by enterocytes, perpetuating a negative feedback for the recruitment of CCR6(+)CD4(+) T cells to the small intestine in treated HIV-1-infected individuals.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Anti-HIV Agents / therapeutic use*
Antiretroviral Therapy, Highly Active
CD4 Antigens / genetics
CD4 Antigens / immunology
Case-Control Studies
Chemokine CCL20 / genetics
Chemokine CCL20 / immunology*
Chemotaxis / drug effects
Chemotaxis / immunology
Enterocytes / drug effects
Enterocytes / immunology
Enterocytes / virology
Feedback, Physiological
Female
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / immunology
Gene Expression Regulation
HIV Infections / drug therapy
HIV Infections / immunology*
HIV Infections / pathology
HIV Infections / virology
HIV-1 / drug effects
HIV-1 / growth & development
Humans
Interleukin-10 / genetics
Interleukin-10 / immunology
Interleukin-17 / genetics
Interleukin-17 / immunology
Intestinal Mucosa / drug effects
Intestinal Mucosa / immunology
Intestinal Mucosa / virology
Intestine, Small / drug effects
Intestine, Small / immunology
Intestine, Small / virology
Lymphocyte Count
Male
Middle Aged
Receptors, CCR6 / deficiency
Receptors, CCR6 / genetics
Receptors, CCR6 / immunology*
Signal Transduction
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / virology
Th17 Cells / drug effects
Th17 Cells / immunology*
Th17 Cells / virology
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / immunology

Substances

Anti-HIV Agents
CCL20 protein, human
CCR6 protein, human
CD4 Antigens
Chemokine CCL20
FOXP3 protein, human
Forkhead Transcription Factors
IL10 protein, human
Interleukin-17
Receptors, CCR6
Transforming Growth Factor beta
Interleukin-10