Foxp3-expressing regulatory T (Treg) cells can suppress the activity of various types of immune cells and play key roles in the maintenance of self-tolerance and in the regulation of immune responses against pathogens and tumor cells. na?ve-like central Treg (cTreg) cells (also known as resting Treg cells) and activated effector Treg (eTreg) cells (also known as activated Treg cells or effector memory Treg cells) [15,16,17,18,19,20]. After maturation, tTreg cells egress the thymus as cTreg cells, which are defined by CD62Lhigh(hi)CD44low(lo) or CC chemokine receptor (CCR7)hiCD44lo phenotypes, circulate in secondary lymphoid organs, depending on the functions of homing receptors CD62L and CCR7 [15,16]. Upon antigen stimulation, cTreg cells differentiate into eTreg cells, which are defined by CD62LloCD44hi or CCR7loCD44hi phenotypes [15,16,21] (Figure 1). eTreg cells express higher levels of Treg effector molecules, such as cytotoxic T cell antigen 4 (CTLA4) and inducible T cell costimulator (ICOS) compared to cTreg cells, which likely contribute to enhanced suppressive activity of eTreg cells [15,16,17,21,22,23,24]. Open in a separate window Figure 1 Upon antigen stimulation, central Treg (cTreg) cells (CD62Lhi CCR7hi CD44lo) differentiate into effector Treg (eTreg) cells (CD62Llo CCR7lo CD44hi) depending on TCR and CD28 signaling. After activation, TCR-dependent transcription factors, such as interferon regulatory factor 4 (IRF4), are induced and regulate the eTreg transcriptional program. In contrast, Foxo1 is inactivated by Akt-signaling, which decreases expression of cTreg-related molecules. Loss of IDO-IN-3 Id2, transcription factor 1 (TCF1), and lymphoid enhancer binding factor 1 (LEF1) expression is a signature of mature eTreg cells. Mature eTreg cells highly express immune suppressive molecules, such as cytotoxic T cell antigen 4 (CTLA4) and inducible T cell costimulator (ICOS). The majority of eTreg cells migrate to and accumulate in non-lymphoid peripheral tissues and IDO-IN-3 inflamed sites, probably due to a decrease in CD62L and CCR7 expression and a concomitant increase in the expression of various chemokine receptors (e.g., CCR4, CCR6, and CCR10) and adhesion molecules (e.g., KLRG1, CD103) [16,17,22,23]. eTreg cells can reside in non-lymphoid peripheral tissues, as tissue Treg cells, and play a role not only in the maintenance of immune homeostasis but also in tissue repair and regeneration [25,26,27,28,29,30,31]. For example, visceral adipose tissue (VAT)-Treg cells accumulate in and suppress the inflammation of adipose tissue, thereby regulating insulin resistance IDO-IN-3 [32,33,34]. In the colon, Treg subsets expressing RAR-related orphan receptor (ROR)t and GATA-binding protein 3 (GATA3) are involved in inhibiting inflammation and tissue repair, respectively [35,36,37]. Thus, each tissue-specific Treg subset exhibits distinct functions and phenotypes, likely due to tissue-specific environmental cues (Figure 2). Open in a separate window Figure 2 Peroxisome-proliferator-activated receptor (PPAR), B cell lymphoma 6 (BCL6), T-bet, GATA-binding protein 3 (GATA3), and RORt regulate the differentiation and function of tissue Treg cells derived from eTreg and peripherally derived Treg (pTreg) cells. Treg cells expressing PPAR, BCL6, or GATA3 mainly differentiate from tTreg cells, while RORt+ Treg cells differentiate from na?ve CD4+ T cells [34,35,36,43,44] and T-bet+ Treg cells likely differentiate from both eTreg and pTreg cells [45,46,47]. These tissue-specific Treg subsets express different functional molecules and play different roles in maintaining tissue homeostasis by suppressing specific immune responses and regulating lipid metabolism and tissue repair. A subset of eTreg cells expressing CXC chemokine receptor 5 (CXCR5), known as follicular regulatory T (Tfr) cells, accumulate in the germinal center (GC) of lymphoid organs and suppress GC reactions that are required for high affinity antibody production of B cells [38,39,40]. In contrast, some CXCR5+ Tfr cells with na?ve-like phenotypes are present in the blood [41]. Unlike other Treg subsets, GC Tfr cells do not express the chain of the interleukin (IL)-2 receptor, CD25 [42]. The TCR repertoire of Tfr cells resembles that of Treg cells rather than Tfh cells, consistent with the notion that most Tfr cells do not differentiate from na?ve CD4 T cells, unlike Tfh cells [43]. cTreg and eTreg cell maintenance relies on IL-2 and ICOS signals, respectively, in secondary lymphoid tissues [15]; however, some tissue-specific Treg cells, including colonic Treg cells, are maintained in an IL-2-dependent manner [48]. Although most Rabbit polyclonal to XIAP.The baculovirus protein p35 inhibits virally induced apoptosis of invertebrate and mammaliancells and may function to impair the clearing of virally infected cells by the immune system of thehost. This is accomplished at least in part by its ability to block both TNF- and FAS-mediatedapoptosis through the inhibition of the ICE family of serine proteases. Two mammalian homologsof baculovirus p35, referred to as inhibitor of apoptosis protein (IAP) 1 and 2, share an aminoterminal baculovirus IAP repeat (BIR) motif and a carboxy-terminal RING finger. Although thec-IAPs do not directly associate with the TNF receptor (TNF-R), they efficiently blockTNF-mediated apoptosis through their interaction with the downstream TNF-R effectors, TRAF1and TRAF2. Additional IAP family members include XIAP and survivin. XIAP inhibits activatedcaspase-3, leading to the resistance of FAS-mediated apoptosis. Survivin (also designated TIAP) isexpressed during the G2/M phase of the cell cycle and associates with microtublules of the mitoticspindle. In-creased caspase-3 activity is detected when a disruption of survivin-microtubuleinteractions occurs eTreg cells require TCR signals for their maintenance, a small subset of antigen-experienced Treg cells known as memory Treg cells can survive even in the absence of cognate antigens in an IL-7-dependent.