Complex regulation of T cell functions during pregnancy is required to ensure materno-fetal tolerance. Here we reveal a novel pathway for the temporary suppression of maternal T cell responses in uncomplicated human pregnancies. Our results show that arginase activity is significantly increased in the peripheral blood of pregnant women and remarkably high arginase activities are expressed in term placentae. High enzymatic activity results in high turnover of its substrate l-arginine and concomitant reduction of this amino acid in the microenvironment. Amino acid deprivation is emerging as a regulatory pathway of lymphocyte responses and we assessed the consequences of this enhanced arginase activity on T cell responses. Arginase-mediated l-arginine depletion induces down-regulation of CD3ζ, the main signalling chain of the TCR, and functional T cell hyporesponsiveness. Importantly, this arginase-mediated T cell suppression was reversible, as inhibition of arginase activity or addition of exogenous l-arginine restored CD3ζ chain expression and T cell proliferation. Thus, l-arginine metabolism constitutes a novel physiological mechanism contributing to the temporary suppression of the maternal immune response during human pregnancy.

Human T-lymphotropic virus type 1 (HTLV-1) is a persistent CD4 ؉ T-lymphotropic retrovirus. Most HTLV-1-infected individuals remain asymptomatic, but a proportion develop adult T cell leukemia or inflammatory disease. It is not fully understood how HTLV-1 persists despite a strong immune response or what determines the risk of HTLV-1-associated diseases. Until recently, it has been difficult to quantify lymphocyte kinetics in humans in vivo. Here, we used deuterated glucose labeling to quantify in vivo lymphocyte dynamics in HTLV-1-infected individuals. We then used these results to address four questions. (i) What is the impact of HTLV-1 infection on lymphocyte dynamics? (ii) How does HTLV-1 persist? (iii) What is the extent of HTLV-1 expression in vivo? (iv) What features of lymphocyte kinetics are associated with HTLV-1-associated myelopathy/tropical spastic paraparesis? We found that CD4 ؉ CD45RO ؉ and CD8 ؉ CD45RO ؉ T lymphocyte proliferation was elevated in HTLV-1-infected subjects compared with controls, with an extra 10 12 lymphocytes produced per year in an HTLV-1-infected subject. The in vivo proliferation rate of CD4 ؉ CD45RO ؉ cells also correlated with ex vivo viral expression. Finally, the inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis was associated with significantly increased CD4 ؉ CD45RO ؉ cell proliferation. We suggest that there is persistent viral gene expression in vivo, which is necessary for the maintenance of the proviral load and determines HTLV-1-associated myelopathy/tropical spastic paraparesis risk. Human T-lymphotropic virus type 1 (HTLV-1) is an exogenous retrovirus that persistently infects 20-30 million people worldwide. It is the etiological agent of adult T cell leukemia and a range of inflammatory diseases including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic disease of the central nervous system. The majority of HTLV-1-infected individuals remain lifelong asymptomatic carriers (ACs) of the virus.HTLV-1 persists despite the large HTLV-1-specific CD8 ϩ cytotoxic T lymphocyte (CTL) response that is observed in most HTLV-1-infected individuals (1, 2). The observation that cellfree virus, viral protein, and viral mRNA are usually undetectable in the blood (3, 4) suggests that HTLV-1 is largely transcriptionally inactive, at least in the periphery. The viral proteins HBZ, Rex, and p30 II (5-7), as well as epigenetic modifications (8), have been shown to regulate HTLV-1 gene expression and could promote this viral latency. However, the observation of HTLV-1-specific CTL responses (1, 9, 10) indicates that there was certainly viral protein expression in the past and that there is probably a degree of ongoing viral expression. Although HTLV-1 reverse transcriptase has an error rate comparable with other retroviruses (11), the HTLV-1 genome is remarkably stable (12), indicating that very few rounds of replication via reverse transcription have occurred. Thus, it appears that HTLV-1 favors a mode of persistence in which...

The CD8+ lymphocyte response is a main component of host immunity, yet it is difficult to quantify its contribution to the control of persistent viruses.

Human T cell lymphotropic virus type 1 (HTLV-1) causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We used interferon- gamma enzyme-linked immunospot assays with overlapping peptides spanning the entire HTLV-1 proteome to test whether the HTLV-1-specific CD8(+) T cells differed significantly in frequency or immunodominance hierarchy between patients with HAM/TSP and asymptomatic carriers and whether the frequency correlated with provirus load. Tax was the immunodominant target antigen. There was no significant qualitative or quantitative difference in the HTLV-1-specific CD8(+) T cell response between the 2 groups. Virus-specific CD8(+) T cell frequency alone does not indicate the effectiveness of the cytotoxic T lymphocyte response in controlling provirus load at equilibrium.

Neuroinflammation can cause major neurological dysfunction, without demyelination, in both multiple sclerosis (MS) and a mouse model of the disease (experimental autoimmune encephalomyelitis; EAE), but the mechanisms remain obscure. Confocal in vivo imaging of the mouse EAE spinal cord reveals that impaired neurological function correlates with the depolarisation of both the axonal mitochondria and the axons themselves. Indeed, the depolarisation parallels the expression of neurological deficit at the onset of disease, and during relapse, improving during remission in conjunction with the deficit. Mitochondrial dysfunction, fragmentation and impaired trafficking were most severe in regions of extravasated perivascular inflammatory cells. The dysfunction at disease onset was accompanied by increased expression of the rate-limiting glycolytic enzyme phosphofructokinase-2 in activated astrocytes, and by selective reduction in spinal mitochondrial complex I activity. The metabolic changes preceded any demyelination or axonal degeneration. We conclude that mitochondrial dysfunction is a major cause of reversible neurological deficits in neuroinflammatory disease, such as MS.