Nting alloimmune and autoimmune disease. The FGL2 cRIIB pathway is also known to be utilized by viruses and tumor cells to evade immune surveillance. Moving HM61713, BI 1482694MedChemExpress Olmutinib forward, therapies based on modulation of the FGL2 cRIIB pathway hold promise for the treatment of a wide variety of conditions ranging from autoimmunity to cancer.KEY WORDS: Autoimmunity, FGL2, transplantation, TregHISTORICAL PERSPECTIVE ON REGULATORY T CELLS A population of suppressive T cells was first postulated in the early 1970s by Gershon and Kondo, who discovered that some T cells could inhibit immune responses in vitro.1 These T cells were termed suppressor T cells and were found to be derived from a distinct population from helper T cells. The inability to define these cells more specifically led the scientific community to lose interest in the concept of “suppressor T cells.” In 1995, Sakaguchi identified CD25, the interleukin (IL)-2 receptor, as a marker for a population of T cells with the ability to inhibit autoimmune responses.2,3 Depletion of CD4+CD25+ T cells led to enhanced autoimmune and alloimmune responses, whereas adoptive transfer of these cells restored tolerance and prevented the development of autoimmune disease. The best characterized regulatory T cells are CD4+CD25+Foxp3+ T cells (Treg). Other regulatory T cell subsets are known to exist and include Tr1, Th3, CD8+, CD8+, NKT cells, T cells, and doublenegative T cells (DNT).4,5 In 2001, a mutation in the Foxp3 gene, an Xlinked transcription factor, was identified as the causative mutation in the Scurfy mouse, which displays a severe autoimmune phenotype.6,7 A mutation in Foxp3 was then found to be responsible for the human disease, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX).8 This disorder is associated with autoimmune enteropathy, dermatitis, nail dystrophy, autoimmune endocrinopathies, and autoimmune skin conditions. This led to the discovery of Foxp3 as the master regulator of Treg development and function. Once Foxp3 is induced, its expression leads to expression of Treg signature genes including Foxp3 itself.9,10 Investigators have focused their attentionon defining the mechanism of action and ability of CD4+CD25+Foxp3+ Treg to induce tolerance. This review will focus on NS-018 web discussing the role of Treg in alloimmunity and autoimmunity, with an emphasis on the Treg effector molecule FGL2. In addition, we will discuss how therapies targeting the FGL2?FcRIIB pathway may be used in various human diseases. MECHANISMS OF TREG-MEDIATED SUPPRESSION OF IMMUNE RESPONSES The CD4+CD25+Foxp3+ Treg have been shown to employ multiple mechanisms to inhibit immune responses.11,12 Some of these mechanisms directly inhibit T effector cells, while others indirectly inhibit T effector cells by acting on antigen-presenting cells (APC) such as dendritic cells (DC) (Figure 1, Table 1). Molecules credited with contributing to Treg suppressive activity include IL-10, TGF-, CD39/CD73, IL-35, and FGL2.12,13 Treg have been shown to bind IL-2 through the high-affinity IL-2 receptor, thereby depriving dividing T cells of IL-2 and promoting apoptosis in these cells.14 Additional studies have shown that Treg can release granzyme B that can result in the apoptosis of activated T cells.15 Certain Treg subsets secrete adenosine that can act through A2A receptors to promote anergy in T cells.16 Treg have also been shown to produce high local levels of cAMP that can be transferred to T cells via gap junctions.Nting alloimmune and autoimmune disease. The FGL2 cRIIB pathway is also known to be utilized by viruses and tumor cells to evade immune surveillance. Moving forward, therapies based on modulation of the FGL2 cRIIB pathway hold promise for the treatment of a wide variety of conditions ranging from autoimmunity to cancer.KEY WORDS: Autoimmunity, FGL2, transplantation, TregHISTORICAL PERSPECTIVE ON REGULATORY T CELLS A population of suppressive T cells was first postulated in the early 1970s by Gershon and Kondo, who discovered that some T cells could inhibit immune responses in vitro.1 These T cells were termed suppressor T cells and were found to be derived from a distinct population from helper T cells. The inability to define these cells more specifically led the scientific community to lose interest in the concept of “suppressor T cells.” In 1995, Sakaguchi identified CD25, the interleukin (IL)-2 receptor, as a marker for a population of T cells with the ability to inhibit autoimmune responses.2,3 Depletion of CD4+CD25+ T cells led to enhanced autoimmune and alloimmune responses, whereas adoptive transfer of these cells restored tolerance and prevented the development of autoimmune disease. The best characterized regulatory T cells are CD4+CD25+Foxp3+ T cells (Treg). Other regulatory T cell subsets are known to exist and include Tr1, Th3, CD8+, CD8+, NKT cells, T cells, and doublenegative T cells (DNT).4,5 In 2001, a mutation in the Foxp3 gene, an Xlinked transcription factor, was identified as the causative mutation in the Scurfy mouse, which displays a severe autoimmune phenotype.6,7 A mutation in Foxp3 was then found to be responsible for the human disease, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX).8 This disorder is associated with autoimmune enteropathy, dermatitis, nail dystrophy, autoimmune endocrinopathies, and autoimmune skin conditions. This led to the discovery of Foxp3 as the master regulator of Treg development and function. Once Foxp3 is induced, its expression leads to expression of Treg signature genes including Foxp3 itself.9,10 Investigators have focused their attentionon defining the mechanism of action and ability of CD4+CD25+Foxp3+ Treg to induce tolerance. This review will focus on discussing the role of Treg in alloimmunity and autoimmunity, with an emphasis on the Treg effector molecule FGL2. In addition, we will discuss how therapies targeting the FGL2?FcRIIB pathway may be used in various human diseases. MECHANISMS OF TREG-MEDIATED SUPPRESSION OF IMMUNE RESPONSES The CD4+CD25+Foxp3+ Treg have been shown to employ multiple mechanisms to inhibit immune responses.11,12 Some of these mechanisms directly inhibit T effector cells, while others indirectly inhibit T effector cells by acting on antigen-presenting cells (APC) such as dendritic cells (DC) (Figure 1, Table 1). Molecules credited with contributing to Treg suppressive activity include IL-10, TGF-, CD39/CD73, IL-35, and FGL2.12,13 Treg have been shown to bind IL-2 through the high-affinity IL-2 receptor, thereby depriving dividing T cells of IL-2 and promoting apoptosis in these cells.14 Additional studies have shown that Treg can release granzyme B that can result in the apoptosis of activated T cells.15 Certain Treg subsets secrete adenosine that can act through A2A receptors to promote anergy in T cells.16 Treg have also been shown to produce high local levels of cAMP that can be transferred to T cells via gap junctions.