The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood

1] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Nature Immunology (Impact Factor: 20). 12/2012; 14(2). DOI: 10.1038/ni.2496
Source: PubMed


CD4(+)CXCR5(+)Foxp3(+) follicular regulatory T cells (T(FR) cells) inhibit humoral immunity mediated by CD4(+)CXCR5(+)Foxp3(-) follicular helper T cells (T(FH) cells). Although the inhibitory receptor PD-1 is expressed by both cell types, its role in the differentiation of T(FR) cells is unknown. Here we found that mice deficient in PD-1 and its ligand PD-L1 had a greater abundance of T(FR) cells in the lymph nodes and that those T(FR) cells had enhanced suppressive ability. We also found substantial populations of T(FR) cells in mouse blood and demonstrated that T(FR) cells in the blood homed to lymph nodes and potently inhibited T(FH) cells in vivo. T(FR) cells in the blood required signaling via the costimulatory receptors CD28 and ICOS but were inhibited by PD-1 and PD-L1. Our findings demonstrate mechanisms by which the PD-1 pathway regulates antibody production and help reconcile inconsistencies surrounding the role of this pathway in humoral immunity.

Download full-text


Available from: Christopher V Carman,
  • Source
    • "PP were harvested from unimmunized mice. Serum was isolated from blood using serum separator tubes (BD vacutainer) and NP-specific IgG measured by ELISA as previously described (Sage et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Defective antibody production in aging is broadly attributed to immunosenescence. However, the precise immunological mechanisms remain unclear. Here, we demonstrate an increase in the ratio of inhibitory T follicular regulatory (TFR) cells to stimulatory T follicular helper (TFH) cells in aged mice. Aged TFH and TFR cells are phenotypically distinct from those in young mice, exhibiting increased programmed cell death protein-1 expression but decreased ICOS expression. Aged TFH cells exhibit defective antigen-specific responses, and programmed cell death protein-ligand 1 blockade can partially rescue TFH cell function. In contrast, young and aged TFR cells have similar suppressive capacity on a per-cell basis in vitro and in vivo. Together, these studies reveal mechanisms contributing to defective humoral immunity in aging: an increase in suppressive TFR cells combined with impaired function of aged TFH cells results in reduced T-cell-dependent antibody responses in aged mice. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 07/2015; 186(2). DOI:10.1016/j.celrep.2015.06.015 · 8.36 Impact Factor
  • Source
    • "Nonetheless, the differential requirements for FOXO1 activity likely explain why Tfr cells derive from tTregs and not pTregs (Chung et al., 2011; Linterman et al., 2011). Naive T cells could not simultaneously receive an ICOS signal and maintain FOXO1 activity—both of which would be required for Tfr differentiation from naive T cells (Hedrick et al., 2012; Sage et al., 2013). Rather, tTregs differentiate into stable Tregs in the thymus, and can thus receive an ICOS signal in peripheral lymphoid organs, which might allow them to inactivate FOXO1 and further differentiate into Tfr cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: T follicular helper (Tfh) cells are essential in the induction of high-affinity, class-switched antibodies. The differentiation of Tfh cells is a multi-step process that depends upon the co-receptor ICOS and the activation of phosphoinositide-3 kinase leading to the expression of key Tfh cell genes. We report that ICOS signaling inactivates the transcription factor FOXO1, and a Foxo1 genetic deletion allowed for generation of Tfh cells with reduced dependence on ICOS ligand. Conversely, enforced nuclear localization of FOXO1 inhibited Tfh cell development even though ICOS was overexpressed. FOXO1 regulated Tfh cell differentiation through a broad program of gene expression exemplified by its negative regulation of Bcl6. Final differentiation to germinal center Tfh cells (GC-Tfh) was instead FOXO1 dependent as the Foxo1(-/-) GC-Tfh cell population was substantially reduced. We propose that ICOS signaling transiently inactivates FOXO1 to initiate a Tfh cell contingency that is completed in a FOXO1-dependent manner. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 02/2015; 42(2):239-51. DOI:10.1016/j.immuni.2015.01.017 · 21.56 Impact Factor
  • Source
    • "In patients infected with Hepatitis C virus, increased PD-1 expression on Tregs correlated with lower Treg numbers and clinical markers of immune modulation, which in vitro could be overcome by blocking PD-L1/PD-1 interactions [16]. Along these lines, it was demonstrated that PD-1 and PD-L1 negatively regulate the differentiation and suppressive functions of a particular Treg subset, namely follicular Tregs [17]. However, other evidence points towards the opposite role of PD-L1/PD-1 signaling in Treg homeostasis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: T cell activation represents a double-edged sword in atherogenesis, as it promotes both pro-inflammatory T cell activation and atheroprotective Foxp3+ regulatory T cell (Treg) responses. Here, we investigated the role of the co-inhibitory receptor programmed cell death-1 (PD-1) in T cell activation and CD4+ T cell polarization towards pro-atherogenic or atheroprotective responses in mice. Mice deficient for both low density lipoprotein receptor and PD-1 (Ldlr-/-Pd1-/-) displayed striking increases in systemic CD4+ and CD8+ T cell activation after 9 weeks of high fat diet feeding, associated with an expansion of both pro-atherogenic IFNγ-secreting T helper 1 cells and atheroprotective Foxp3+ Tregs. Importantly, PD-1 deficiency did not affect Treg suppressive function in vitro. Notably, PD-1 deficiency exacerbated atherosclerotic lesion growth and entailed a massive infiltration of T cells in atherosclerotic lesions. In addition, aggravated hypercholesterolemia was observed in Ldlr-/-Pd1-/- mice. In conclusion, we here demonstrate that although disruption of PD-1 signaling enhances both pro- and anti-atherogenic T cell responses in Ldlr-/- mice, pro-inflammatory T cell activation prevails and enhances dyslipidemia, vascular inflammation and atherosclerosis.
    PLoS ONE 04/2014; 9(4):e93280. DOI:10.1371/journal.pone.0093280 · 3.23 Impact Factor
Show more