CCR8⁺FOXp3⁺T_regcells as master drivers of immune regulation

Abstract

The current study identifies CCR8 regulatory T cells (T cells) as drivers of immunosuppression. We show that in human peripheral blood cells, more than 30% of T up-regulate CCR8 following activation in the presence of CCL1. This interaction induces STAT3-dependent up-regulation of FOXp3, CD39, IL-10, and granzyme B, resulting in enhanced suppressive activity of these cells. Of the four human CCR8 ligands, CCL1 is unique in potentiating T cells. The relevance of these observations has been extended using an experimental model of multiple sclerosis [experimental autoimmune encephalomyelitis, (EAE)] and a stabilized version of mouse CCL1 (CCL1-Ig). First, we identified a self-feeding mechanism by which CCL1 produced by T cells at an autoimmune site up-regulates the expression of its own receptor, CCR8, on these cells. Administration of CCL1-Ig during EAE enhanced the in vivo proliferation of these CCR8 regulatory cells while inducing the expression of CD39, granzyme B, and IL-10, resulting in the efficacious suppression of ongoing EAE. The critical role of the CCL1-CCR8 axis in T cells was further dissected through adoptive transfer studies using CCR8 mice. Collectively, we demonstrate the pivotal role of CCR8 T cells in restraining immunity and highlight the potential clinical implications of this discovery.

Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target?

“…Treg cells are chemoattracted by chemokine gradients . CCR4, CCR8, CCR10, and CXCR3 are chemokine receptors responsible for Treg cell migration to the TME in response to CC and CXC chemokines: CCR4 is bound by CCL17 and CCL22, CCR8 is bound by CCL1, CCR10 is bound by CCL28, and CXCR3 is activated by CXCL9/10/11 . Thymus‐derived Treg cells preferentially recognize self‐antigens by high‐affinity TCR and clonally expand in the TME.…”

“…Increased expression of CCR8, a receptor for CCL1, is observed in Treg cells and NKT cells, particularly in cancer patients, and faint expression is observed in CD8 + T cells or Th1 cells. Interactions between CCL1 and CCR8 enhance the expression of FoxP3 through the STAT3 pathway, and activated CCR8 + Treg cells strongly suppress antitumor immunity by promoting ATP‐adenosine metabolism by CD39 and secretion of IL‐10 and granzyme B . The overall survival of breast cancer patients with a high infiltration of CCR8 + FoxP3 + Treg cells is significantly shorter than that of patients with low infiltration .…”

“…of FoxP3 through the STAT3 pathway, and activated CCR8 + Treg cells strongly suppress antitumor immunity by promoting ATP-adenosine metabolism by CD39 and secretion of IL-10 and granzyme B. 29 The overall survival of breast cancer patients with a high infiltration of CCR8 + FoxP3 + Treg cells is significantly shorter than that of patients with low infiltration. 64 Therefore, therapies that target CCL1-CCR8 molecules warrant testing in the clinic.…”

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

“…Interestingly, stimulation with its cognate ligand CCL1, but not other CCR8 ligands such as CCL8, CCL16 and CCL18, enhanced suppressive capacity of human Treg cells in vitro in a signal transducer and activator of transcription 3 (STAT3)‐dependent manner . Moreover, CCR8 + Treg cells up‐regulate CCL1 expression, thereby possibly promoting a positive paracrine feedback loop to sustain their suppressive potential in situ .…”

“…Interestingly, stimulation with its cognate ligand CCL1, but not other CCR8 ligands such as CCL8, CCL16 and CCL18, enhanced suppressive capacity of human Treg cells in vitro in a signal transducer and activator of transcription 3 (STAT3)‐dependent manner . Moreover, CCR8 + Treg cells up‐regulate CCL1 expression, thereby possibly promoting a positive paracrine feedback loop to sustain their suppressive potential in situ . Targeting CCR8 + Treg cells through either anti‐CCR8 mAb or anti‐CCL1 neutralizing mAb drastically reduced tumor‐infiltrating Treg cells while robustly enhancing the anti‐tumor immune response against murine tumor models such as colorectal adenocarcinoma .…”