Yu-Hwa Huang

Specific central nervous system recruitment of HLA-G+ regulatory T cells in multiple sclerosis†

We have recently described a novel population of natural regulatory T cells (Treg) that are characterized by the expression of HLA‐G and may be found at sites of tissue inflammation (HLA‐Gpos Treg). Here we studied the role of these cells in multiple sclerosis (MS), a prototypic autoimmune inflammatory disorder of the central nervous system (CNS).

T cell suppression by naturally occurring HLA-G-expressing regulatory CD4+ T cells is IL-10-dependent and reversible

CD4+ T cells constitutively expressing the immune‐tolerogenic HLA‐G have been described recently as a new type of nTreg (HLA‐Gpos Treg) in humans. HLA‐Gpos Treg accumulate at sites of inflammation and are potent suppressors of T cell proliferation in vitro, suggesting their role in immune regulation. We here characterize the mechanism of how CD4+ HLA‐Gpos Treg influence autologous HLA‐Gneg Tresp function. Using a suppression system free of APC, we demonstrate a T–T cell interaction, resulting in suppression of HLA‐Gneg Tresp, which is facilitated by TCR engagement on HLA‐Gpos Treg. Suppression is independent of cell–cell contact and is reversible, as the removal of HLA‐Gpos Treg from the established coculture restored the proliferative capability of responder cells. Further, HLA‐Gpos Treg‐mediated suppression critically depends on the secretion of IL‐10 but not TGF‐β.

Postpartum-activation of multiple sclerosis is associated with down-regulation of tolerogenic HLA-G

We used microarray analysis to obtain insights into the immuno-regulatory mechanisms controlling pregnancy-associated MS disease activity. We studied expression levels of 5000 immune-related genes in peripheral blood mononuclear cells in patients with relapsing-remitting MS during pregnancy and postpartum and in comparison to controls. In the microarray analysis, HLA-G, a non-classical major histocompatibility molecule mainly attributed with immune-tolerogenic functions, was found differentially regulated between MS patients and controls. The finding was corroborated and extended by real-time PCR, flow-cytometry and ELISA in a larger patient sample. The results delineate an important role for the immune-tolerogenic molecule HLA-G in modulating disease activity and pregnancy-related changes in MS patients.

CEACAM1 dampens antitumor immunity by down-regulating NKG2D ligand expression on tumor cells

By retaining NKG2D ligands within tumor cells, carcinoembryonic antigen–related cell adhesion molecule 1 (CEACAM1) facilitates tumor cell escape from NK cell–mediated cytolysis in vitro and in vivo.

The Short Isoform of the CEACAM1 Receptor in Intestinal T Cells Regulates Mucosal Immunity and Homeostasis via Tfh Cell Induction

Carcinoembryonic antigen cell adhesion molecule like I (CEACAM1) is expressed on activated T cells and signals through either a long (L) cytoplasmic tail containing immune receptor tyrosine based inhibitory motifs, which provide inhibitory function, or a short (S) cytoplasmic tail with an unknown role. Previous studies on peripheral T cells show that CEACAM1-L isoforms predominate with little to no detectable CEACAM1-S isoforms in mouse and human. We show here that this was not the case in tissue resident T cells of intestines and gut associated lymphoid tissues, which demonstrated predominant expression of CEACAM1-S isoforms relative to CEACAM1-L isoforms in human and mouse. This tissue resident predominance of CEACAM1-S expression was determined by the intestinal environment where it served a stimulatory function leading to the regulation of T cell subsets associated with the generation of secretory IgA immunity, the regulation of mucosal commensalism, and defense of the barrier against enteropathogens.

CEACAM1 on activated NK cells inhibits NKG2D-mediated cytolytic function and signaling

Carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) is expressed on activated natural killer (NK) cells wherein it inhibits lysis of CEACAM1‐bearing tumor cell lines. The mechanism for this is unknown. Here, we show that interleukin‐2‐induced expression of CEACAM1 on both mouse and primary human NK cells impairs the ability of NK gene complex group 2 member D (NKG2D) to stimulate cytolysis of CEACAM1‐bearing cells. This process requires the expression of CEACAM1 on the NK cells and on the tumor cells, which is consistent with the involvement of trans‐homophilic interactions between CEACAM1. Mechanistically, co‐engagement of NKG2D and CEACAM1 results in a biochemical association between these two surface receptors and the recruitment of Src homology phosphatase 1 by CEACAM1 that leads to dephosphorylation of the guanine nucleotide exchange factor Vav1 and blockade of downstream signaling that is associated with the initiation of cytolysis. Thus, CEACAM1 on activated NK cells functions as an inhibitory receptor for NKG2D‐mediated cytolysis, which has important implications for understanding the means by which CEACAM1 expression adversely affects tumor immunity.

Janus head: the dual role of HLA-G in CNS immunity

The central nervous system (CNS) is considered an immune-privileged organ that maintains an adaptable immune surveillance system. Dysregulated immune function within the CNS contributes to the development of brain tumor growth, and robust immune activation results in excessive inflammation. Human lymphocyte antigen-G (HLA-G) proteins with tolerogenic immunoreactivity have been implicated in various pathophysiological processes including immune surveillance, governing homeostasis and immune regulation. In this review, we describe the wealth of evidence for the involvement of HLA-G in the CNS under physiological and pathological conditions. Further, we review regulatory functions that may be applicable as beneficial strategies in the therapeutic manipulation of immune-mediated CNS immune responses. Additionally, we try to understand how this molecule cooperates with other CNS-resident cells to maintain normal immune homeostasis, while still facilitating the development of the appropriate immune responses.

CEACAM1 as a multi-purpose target for cancer immunotherapy

ABSTRACT CEACAM1 is an extensively studied cell surface molecule with established functions in multiple cancer types, as well as in various compartments of the immune system. Due to its multi-faceted role as a recently appreciated immune checkpoint inhibitor and tumor marker, CEACAM1 is an attractive target for cancer immunotherapy. Herein, we highlight CEACAM1s function in various immune compartments and cancer types, including in the context of metastatic disease. This review outlines CEACAM1s role as a therapeutic target for cancer treatment in light of these properties.

Corrigendum: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion

This corrects the article DOI: 10.1038/nature13848

Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have functional efficacy

ABSTRACT Both in vivo data in preclinical cancer models and in vitro data with T cells from patients with advanced cancer support a role for Tim-3 blockade in promoting effective anti-tumor immunity. Consequently, there is considerable interest in the clinical development of antibody-based therapeutics that target Tim-3 for cancer immunotherapy. A challenge to this clinical development is the fact that several ligands for Tim-3 have been identified: galectin-9, phosphatidylserine, HMGB1, and most recently, CEACAM1. These observations raise the important question of which of these multiple receptor:ligand relationships must be blocked by an anti-Tim-3 antibody in order to achieve therapeutic efficacy. Here, we have examined the properties of anti-murine and anti-human Tim-3 antibodies that have shown functional efficacy and find that all antibodies bind to Tim-3 in a manner that interferes with Tim-3 binding to both phosphatidylserine and CEACAM1. Our data have implications for the understanding of Tim-3 biology and for the screening of anti-Tim-3 antibody candidates that will have functional properties in vivo.