Originally discovered as a T cell-activating molecule, 4-1BB (CD137) is now also recognized as an activator of non-T cells, thus imparting a new dimension to its potential effects. prevention of activation-induced cell death and induction of anti-apoptotic genes.6 There is a disparity between its and effects. While it supports the activation of both CD4+ and CD8+ T cells and kills CD4+ T cells or inactivates their effector functions.7 Much progress has been made in understanding the basis of the biased 4-1BB effects, and several causative molecules have been indentified, the main players being interferon (IFN)-,8, 9, 10 tumor buy NU7026 necrosis factor (TNF)-,8 buy NU7026 transforming growth factor-,11, 12 and indoleamine 2,3-dioxygenase.13, 14 Nearly a decade after the discovery of 4-1BB, two groups demonstrated functional expression of 4-1BB on DCs,4, 15 an attribute somewhat conflicting with its proposed role as a T cell-activating molecule.2, 3 In the years that followed, functional expression of 4-1BW was noted on several non-T cells including monocytes, neutrophils, macrophages, W cells and natural killer (NK) cells (see below). The identification of functional 4-1BW expression on non-T cells is usually important not only for understanding the effects of 4-1BW but also for helping to design effective therapeutic strategies against a variety of T cell- buy NU7026 as well as non-T cell-mediated immune diseases. The effects of anti-4-1BW antibody (Ab) on T cells have been extensively investigated and unifying theories have been proposed as to their mechanistic basis. A comprehensive review dealing with the various effects of anti-4-1BW on non-T cells, however, is usually lacking. In this review we will focus on the functions of 4-1BW in non-T cells including DCs, monocytes, neutrophils, W cells and NK cells, and discuss how its expression might be manipulated to treat various immune diseases. Effects of 4-1BW crosslinking in non-T cells Dendritic cells DCs are potent antigen-presenting cells that possess the ability to stimulate naive T cells.16 Besides showing antigens to T cells, activated DCs secrete a variety of immune modulators that have buy NU7026 manifold functions in health and disease.17 Of all the non-T cells studied to date, the function of 4-1BB has been most extensively studied in DCs. Futugawa anti-CD40 downregulates this expression. These authors suggested that signaling 4-1BW using 4-1BW ligand (4-1BBL)-transfected cells upregulates W7-1 and W7-2, and increases IL-6 and IL-12 secretion by DCs.15 That 4-1BB transmits activation signals through 4-1BB in DCs was demonstrated by the absence of IL-12 production in response to anti-CD40 when the 4-1BB/4-1BBL interaction was blocked by anti-4-1BBL.15 Confirmation that DCs express functional 4-1BB came from Wilcox agonistic anti-4-1BB monoclonal antibody (mAb) to naive mice enhanced the ability of DCs to stimulate T cell-proliferative responses to both alloantigens and nominal antigens.4 In addition, Zhang activation of DCs by anti-4-1BW led to phosphorylation of STAT3, which in turn strengthened CD8+ T-cell responses augmenting viral clearance, and this effect was corroborated using STAT3 conditional knockout mice.18 Interestingly, 4-1BB?/? mice have increased frequencies of DCs,19 but these DCs have decreased survival rates,20 highlighting the importance of 4-1BW in DC regulation. Taken together, these findings show that 4-1BW ligation by agonistic anti-4-1BW on DCs has important effects. Monocytes Monocytes are bone marrow-derived immature macrophages. They have a distinct phenotype, and upon maturation are involved in killing bacteria and tumors by producing cytokines and other immune modulators.21 In 1995, Schwarz or (unpublished observations). Nevertheless, the identification of functional 4-1BW on W hDx-1 cells is usually an important obtaining and perhaps explains why B-cell numbers/function are affected in mice treated with anti-4-1BW alone or in combination with autoimmune-inducing proteins.8 Neutrophils Neutrophils, components of the innate immune system, are produced in huge numbers in response to infection, trauma and inflammation, and form an early line of defense against bacterial and parasitic infections by releasing immune modulators and various cytokines.29, 30 Murine neutrophils constitutively express 4-1BB.31 stimulation of purified neutrophils with either anti-4-1BB alone or in combination with heat-killed enhanced production of IL-6 and TNF- as well as IL-1, IL-1R,.