Expanding Role of T-Cell Costimulators in Regulatory T-Cell Function: Recent Advances in Accessory Molecules Expressed on Both Regulatory and Nonregulatory T Cells

Abstract

A subpopulation of T cells harbors a suppressor phenotype and can significantly dampen autoreactive CD4+ and CD8+ T-cell responses. These regulatory T (Treg) cells, which can arise naturally in the thymus and encompass a CD25+CD4+ T-cell repertoire or be antigenically induced, are central players in the maintenance of self-tolerance. A plethora of O-cell costimulatory and accessory receptor molecules expressed by Treg and/or non-regulatory T cells, such as GITR, OX40, and CTLA-4, are involved in modulating the pathogenesis of numerous autoimmune disorders, transplant rejection, and tumor immunity, as well as the control of infections. Exciting new evidence shows that O-cell costimulators, some of which are identified as hopeful discriminative Treg-cell markers, appear to mediate Treg-cell homeostasis and function. Understanding the biological significance of the O-cell costimulatory molecules and the accessory molecules expressed by Treg cells is a prerequisite to better characterizing this regulatory T-cell population. We provide a synopsis of the current understanding of several costimulatory molecules that can orchestrate the function of both naturally arising and antigen-inducible Treg cells.

Co‐inhibitory roles for glucocorticoid‐induced TNF receptor in CD1d‐dependent natural killer T cells

“…GITR most closely resembles OX40 in the protein and gene structures and in immunological roles [6,7,[27][28][29][30][31][32]. In addition, the genomes for OX40 and GITR might be evolutionarily derived from one gene because these genes are contiguously located on the same chromosomal locus, suggesting the redundant roles between OX40 and GITR.…”

“…Among them, glucocorticoid-induced TNF receptor (GITR) seems unique for its bidirectional effects on T cell and NK cell activation. GITR was initially identified as a costimulatory molecule for T cell activation [4], and the agonistic anti-GITR mAb, DTA-1, enhances T cell responses in several disease models, such as tumor rejection, autoimmune reaction, GVH disease, and viral infection [5][6][7]. However, several observations have shown that GITR signals can serve as an inhibitory factor in T cell responses.…”

Presence of Functional Mouse Regulatory CD4+CD25+T Cells in Xenogeneic Neonatal Porcine Thymus-Grafted Athymic Mice

“…CD4 + CD25 + Treg cells represent approximately 10% of peripheral CD4 + T cells in mice and humans. In addition to the expression of CD25 molecule, mouse Treg cells are also characterized by the constitutive expressions of glucocorticoid-induce tumor necrosis factor receptor (GITR), cytotoxic T-lymphocyte-associated protein 4(CTLA4), CD45RB, CD122, CCR8, toll-like receptor-8, Foxp3 and CD103 molecules (3,8). However, it should be noted that many of these molecules are usually expressed by activated/memory nonTreg, too.…”

T-cell Receptor CDR3 Sequence but Not Recognition Characteristics Distinguish Autoreactive Effector and Foxp3+ Regulatory T-cells

“…Sakaguchi et al first proposed that a subset of CD4 + T-cells, that constitutively express the CD25 antigen (IL-2R chain), function as regulatory T-cells in the normal mouse (Asano et al, 1996;Sakaguchi et al, 1995;Suri-Payer et al, 1998) T-cells express slightly higher levels of CD5, cytotoxic T-lymphocyte antigen (CTLA-4) and glucocorticoid-induced TNF-like receptor (GITR), lymphocyte-activation gene (LAG-3), 4-1BB, CD28, CD134, CD80/86 (B7) as well as intermediate and low levels of CD45RB. However, none of those is restricted to Treg cells (Ndhlovu et al, 2004;Paust et al, 2004;Workman et al, 2009). One unique feature of Treg cells is that they express the X chromosome-encoded forkhead transcription factor 3 (Foxp3), which serves as a key player in the biology of CD4 + CD25 + Treg cells (Brunkow et al, 2001;Fontenot et al, 2003;Hori et al, 2003;Khattri et al, 2003).…”