Recognition of a New ARTC1 Peptide Ligand Uniquely Expressed in Tumor Cells by Antigen-Specific CD4+ Regulatory T Cells

Abstract

CD4+ regulatory T (Treg) cells play an important role in the maintenance of immunological self-tolerance by suppressing immune responses against autoimmune diseases and cancer. Yet very little is known about the natural antigenic ligands that preferentially activate CD4+ Treg cells. Here we report the establishment of tumor-specific CD4+ Treg cell clones from tumor-infiltrating lymphocytes (TILs) of cancer patients, and the identification of an Ag recognized by Treg cells (ARTC1) gene encoding a peptide ligand recognized by tumor-specific TIL164 CD4+ Treg cells. The mutations in a gene encoding an ARTC1 in 164mel tumor cells resulted in the translation of a gene product containing the peptide ligand recognized by CD4+ Treg cells. ARTC1 peptide-activated CD4+ Treg cells suppress the physiological function (proliferation and IL-2 secretion) of melanoma-reactive T cells. Furthermore, 164mel tumor cells, but not tumor lysates pulsed on B cells, were capable of activating TIL164 CD4+ Treg cells. These results suggest that tumor cells may uniquely present an array of peptide ligands that preferentially recruit and activate CD4+ Treg cells in sites where tumor-specific self-peptide is expressed, leading to the induction of local and tumor-specific immune suppression.

Human Tumor Antigen-Specific Helper and Regulatory T Cells Share Common Epitope Specificity but Exhibit Distinct T Cell Repertoire

“…The first group includes Tregs that act in a cell-to-cell contact-mediated fashion as is the case for CGA-specific Tregs identified in the current study (12,13). In contrast, another group of human TA-specific Tregs like WT-1-specific and EBNA1-specific Tregs appear to act in a soluble factor-dependent fashion (14,41).…”

“…However, the identity of these Ags remains largely unknown. One major finding was the identification of TAderived epitopes encoded by two cancer-germline Ags (CGAs), LAGE-1 and ARTC1, that were recognized by human TA-specific Tregs isolated from TILs of melanoma patients (12,13). Most recently, the Wilm's TA overexpressed by leukemias was shown to stimulate TA-specific Treg clones generated in vitro from PBLs of normal donors (14).…”

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

“…Wang et al were the first to isolate human tumor-associated antigen (TAA)-specific Tregs, in particular Tregs that were specific for the cancer/testis antigen LAGE1 among the TILs of melanoma patients [83]. One year later, the same authors identified Tregs that specifically recognized the ARTC-1 peptide [84]. Another group has successfully detected-again in melanoma patients-circulating Tregs that were specific for multiple distinct melanoma-associated antigens including the glycoprotein 100 (gp100), tyrosinase-related protein 1 (TRP1), the cancer/testis antigen NY-ESO-1 and the anti-apoptotic protein survivin [85].…”

Harnessing the immune response to treat cancer

“…Although other types of suppressive cell have been identified, most regulatory T cells are characterized by expression of surface CD25 and by intracellular FOXP3, a transcription factor that mediates many of their inhibitory capabilities (Fontenot et al, 2005). It is unclear what proportion of Tregs react with specificity to tumour antigens (Wang et al, 2005), or whether they are recruited through the recognition of shared self-antigens that are co-expressed by tumour cells (Nishikawa et al, 2003;Darrasse-Jeze et al, 2009). Tregs can inhibit effector T-cell responses during both the induction (Darrasse-Jeze et al, 2009) and the effector stages (Huehn et al, 2004;Sarween et al, 2004) by a number of mechanisms, such as through direct ligation of CTLA-4 with CD80 or CD86 on effector T cells, by promoting the development of inhibitory DCs, or through the generation of inhibitory cytokines, transforming growth factor-b and IL10 (von Boehmer, 2005).…”