Macrophages (Mφ) are prominent components of solid tumors and exhibit distinct phenotypes in different microenvironments. We have recently found that tumors can alter the normal developmental process of Mφ to trigger transient activation of monocytes in peritumoral stroma. We showed that a fraction of monocytes/Mφ in peritumoral stroma, but not in cancer nests, expresses surface PD-L1 (also termed B7-H1) molecules in tumors from patients with hepatocellular carcinoma (HCC). Monocytes activated by tumors strongly express PD-L1 proteins with kinetics similar to their activation status, and significant correlations were found between the levels of PD-L1+ and HLA-DRhigh on tumor-infiltrating monocytes. Autocrine tumor necrosis factor α and interleukin 10 released from activated monocytes stimulated monocyte expression of PD-L1. The PD-L1+ monocytes effectively suppressed tumor-specific T cell immunity and contributed to the growth of human tumors in vivo; the effect could be reversed by blocking PD-L1 on those monocytes. Moreover, we found that PD-L1 expression on tumor-infiltrating monocytes increased with disease progression, and the intensity of the protein was associated with high mortality and reduced survival in the HCC patients. Thus, expression of PD-L1 on activated monocytes/Mφ may represent a novel mechanism that links the proinflammatory response to immune tolerance in the tumor milieu.

IL-12 is a cytokine that can exert regulatory effects on T and NK cells and promote Th1 responses. To delineate further the physiologic role of IL-12 in immunity, mice deficient for this cytokine were generated. IL-12-deficient mice were impaired but not completely lacking in the ability to produce IFN gamma following endotoxin administration and to mount a Th1 response in vivo, as measured by antigen-induced IFN gamma secretion by immune lymph node cells in vitro. In contrast, secretion of IL-4 was enhanced, while proliferation and secretion of IL-2 and IL-10 were normal following antigen stimulation. DTH responses were significantly reduced in IL-12-deficient mice, but no defect in allogeneic CTL responses was observed. These results indicate that IL-12 plays an essential role in regulating IFN gamma production and in facilitating normal DTH responses. However, other phenomena associated with Th1 responses and cell-mediated immunity, i.e., IL-2 secretion and CTL generation, were not compromised in the absence of IL-12.

IntroductionThe development and differentiation of immune cells is carefully orchestrated by an array of cytokines. Signal transducers and activators of transcription (Stats) represent a small but critical family of transcription factors that play important roles in transmitting cytokine signals. Consequently, Stats are critical for immunoregulation and the development of immune cells. 1,2 Stat5a and Stat5b are two closely related proteins that have overlapping functions with respect to lymphoid development and differentiation. 3,4 Gene targeting of Stat5a and Stat5b (collectively referred to as Stat5), results in impairment in the development of T, B, and natural killer (NK) cells. [5][6][7] In mice in which the amino termini of Stat5a and Stat5b are deleted (denoted as Stat5 ⌬N mice), major disruption of various immune cell parameters was noted. 8,9 However, residual Stat5 function permits T cell development, albeit suboptimally. 10 This contrasts with the complete absence of Stat5a/b, which results in dramatic reduction in thymocyte numbers, in part due to effects on lymphoid stem cell function. 5 T regulatory (Treg) cells comprise a population of cells enriched in CD4 ϩ CD25 ϩ T cells that suppresses T-cell proliferation and function and attenuates immune responses against self-or nonself-antigens. [11][12][13] Naturally arising Treg cells are produced in the thymus as a functionally distinct T-cell subpopulation, whereas adaptive Treg cells are induced from naive T cells after antigen exposure in the periphery. [14][15][16][17] In classic studies, mice develop organ-specific autoimmune disease following neonatal thymectomy, which is corrected by reconstitution with CD4 ϩ CD25 ϩ T cells. 13 The essential role of Treg cells in maintaining tolerance has been confirmed by findings that defective function of this subset is a feature of many models of autoimmunity. 18 More recently, it was discovered independently by several groups that a subset of CD4 ϩ CD25 ϩ T cells expresses the transcription factor Foxp3, which is necessary and sufficient for Treg cell development and function. [19][20][21][22] Foxp3 is highly conserved in mice and humans. Mutation of Foxp3 in mice (scurfy) results in early autoimmune disease, 23 whereas mutations of human Foxp3 are associated with a disorder known as immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX). 24 In mice, Foxp3 is a reliable marker for the Treg lineage.Multiple lines of evidence have indicated that IL-2 is an important growth factor for Treg development and maintenance. Mice lacking IL-2 or its receptor subunits, IL-2R␣ (CD25) and IL-2R␤ (CD122), have deficits in CD4 ϩ CD25 ϩ Treg cells and develop autoimmune disease similar to Foxp3 Ϫ/Ϫ mice. [25][26][27] However, IL-2 is dispensable for Treg cell development, as some Foxp3-expressing cells are present in Il2 Ϫ/Ϫ and Il2ra Ϫ/Ϫ mice, suggesting the involvement of other cytokines. 28 In vitro culture of CD4 ϩ T cells with transforming growth factor-␤1 (TGF-␤1) can promote the generation o...

We have identified a cDNA from a human phytohemagglutinin-activated lymphoblast library encoding a protein that binds 125

No abstract

We studied here the long-term maintenance of distinct populations of T helper type 1 (T(H)1)-lineage cells in vivo and found that effector T(H)1 cells, defined by their secretion of interferon-gamma (IFN-gamma), are short-lived and do not efficiently develop into long-term memory T(H)1 cells. In contrast, a population of activated T(H)1-lineage cells that did not secrete IFN-gamma after primary antigenic stimulation persisted for several months in vivo and developed the capacity to secrete IFN-gamma upon subsequent stimulation. These data suggest that a linear differentiation pathway, as defined by the transition from IFN-gamma-producing to resting memory cells, is relatively limited in vivo and support a revised model for T(H)1 memory differentiation.

Accumulating evidence has demonstrated that tumor necrosis factor-alpha (TNF-alpha) plays an important role in neuropathic pain. Recently, it has been shown that Lumbar 5 ventral root transection (L5 VRT) induces persistent mechanical allodynia and thermal hyperalgesia in bilateral hind paws. In the present study, the role of TNF-alpha in the L5 VRT model was investigated. We found that immunoreactivity (IR) of TNF-alpha and TNF receptor 1 (TNFR1) in ipsilateral (but not in contralateral) L4 and L5 dorsal root ganglion (DRG) was increased following L5 VRT, started 1 day after the lesion and persisted for 2 weeks. Double immunofluorescence staining revealed that the increased TNF-alpha-IR in DRG was in satellite glial cells, immune cells and neuronal cells, while TNFR1-IR was almost restricted at DRG neuronal cells. L5 VRT increased TNF-alpha-IR and TNFR1-IR in bilateral L5 spinal dorsal horn, started 1 day after lesion and persisted for 2 weeks. The increased TNF-alpha-IR in spinal dorsal horn was observed in astrocytes, microglias and neurons, but the upregulation of TNFR1 was mainly in neurons. Intraperitoneal injection of thalidomide, an inhibitor of TNF-alpha synthesis, started at 2h before surgery, blocked mechanical allodynia and thermal hyperalgesia. However, the drug failed to reverse the abnormal pain behaviors, when it was applied at day 7 after surgery. These data suggest that the upregulation of TNF-alpha and TNFR1 in DRG and spinal dorsal horn is essential for the initiation but not for maintenance of the neuropathic pain induced by L5 VRT.

Patients with chronic pain usually suffer from working memory deficits, which may decrease their intellectual ability significantly. Despite intensive clinical studies, the mechanism underlying this form of memory impairment remains elusive. In this study, we investigated this issue in the spared nerve injury (SNI) model of neuropathic pain, a most common form of chronic pain. We found that SNI impaired working memory and short-term memory in rats and mice. To explore the potential mechanisms, we studied synaptic transmission/plasticity in hippocampus, a brain region critically involved in memory function. We found that frequency facilitation, a presynaptic form of short-term plasticity, and long-term potentiation at CA3-CA1 synapses were impaired after SNI. Structurally, density of presynaptic boutons in hippocampal CA1 synapses was reduced significantly. At the molecular level, we found that tumor necrosis factor-α (TNF-α) increased in cerebrospinal fluid, in hippocampal tissue and in plasma after SNI. Intracerebroventricular or intrahippocampal injection of recombinant rat TNF mimicked the effects of SNI in naive rats, whereas inhibition of TNF-α or genetic deletion of TNF receptor 1 prevented both memory deficits and synaptic dysfunction induced by SNI. As TNF-α is critical for development of neuropathic pain, we suggested that the over-production of TNF-α following peripheral nerve injury might lead to neuropathic pain and memory deficits, simultaneously.