With increasing age, the competence of the immune system to fight infections and tumors declines. Age-dependent changes have been mostly described for human CD8 T cells, raising the question of whether the response patterns for CD4 T cells are different. Gene expression arrays of memory CD4 T cells yielded a similar age-induced fingerprint as has been described for CD8 T cells. In crosssectional studies, the phenotypic changes were not qualitatively different for CD4 and CD8 T cells, but occurred much more frequently in CD8 T cells. Homeostatic stability partially explained this lesser age sensitivity of CD4 T cells. With aging, naïve and central memory CD8 T cells were lost at the expense of phenotypically distinct CD8 effector T cells, while effector CD4 T cells did not accumulate. However, phenotypic shifts on central memory T cells were also more pronounced in CD8 T cells. This distinct stability in cell surface marker expression can be reproduced in vitro. The data show that CD8 T cells are age sensitive by at least two partially independent mechanisms: fragile homeostatic control and gene expression instability in a large set of regulatory cell surface molecules.

T cell-dependent B-cell responses decline with age, suggesting defective CD4 T-cell function. CD4 memory T cells from individuals older than 65 y displayed increased and sustained transcription of the dual-specific phosphatase 4 (DUSP4) that shortened expression of CD40-ligand (CD40L) and inducible T-cell costimulator (ICOS) (both P < 0.001) and decreased production of IL-4, IL-17A, and IL-21 (all P < 0.001) after in vitro activation. In vivo after influenza vaccination, activated CD4 T cells from elderly individuals had increased DUSP4 transcription (P = 0.002), which inversely correlated with the expression of CD40L (r = 0.65, P = 0.002), ICOS (r = 0.57, P = 0.008), and IL-4 (r = 0.66, P = 0.001). In CD4 KO mice reconstituted with DUSP4 OT-II T cells, DUSP4 had a negative effect on the expansion of antigen-specific B cells (P = 0.003) and the production of ovaspecific antibodies (P = 0.03) after immunization. Silencing of DUSP4 in memory CD4 T cells improved CD40L (P < 0.001), IL-4 (P = 0.007), and IL-21 (P = 0.04) expression significantly more in the elderly than young adults. Consequently, the ability of CD4 memory T cells to support B-cell differentiation that was impaired in the elderly (P = 0.004) was restored. Our data suggest that increased DUSP4 expression in activated T cells in the elderly in part accounts for defective adaptive immune responses.immunosenescence | signaling | aging W ith increasing age, the ability of the immune system to protect against new antigenic challenges or control chronic infections erodes (1, 2). Incidence and severity of viral infections increase, and the response to prophylactic vaccination declines. More than 90% of all influenza-related deaths in the United States occur in the elderly (3). Vaccine-induced protection for influenza infection is between 20% and 50% in the elderly dependent on age and study compared with ∼90% in young adults (4). In a review of 31 vaccine antibody response studies, the odds ratios to seroconvert or develop seroprotective antibody titers in elderly vs. young adults ranged from 0.24 to 0.59 (5). Epidemiological studies did not find an impact of the increasing compliance with annual flu vaccination on seasonal mortality between 1968 and 2001, further questioning their efficacy (6). The mechanisms accounting for this defective vaccine response have not been identified but likely involve B as well as T cells. Given that the vast majority of adults have had previous exposure to influenza and that antigenic drifts and shifts of the influenza virus involve B-rather than T-cell epitopes, the T-cell defect seems to lie in CD4 memory rather than naïve T-cell function (7). A decline in the frequency and function of virusspecific memory CD4 T cells is also responsible for the increasing incidence of herpes zoster with age caused by the Varicella zoster virus (VZV) (8). VZV is an α-herpes virus that causes chicken pox in children and establishes latency in sensorineural ganglions. On reactivation of VZV from latency, virus is transported along neuronal a...

ABSTRACT:␥-Hydroxybutyric acid (GHB), a drug of abuse, is a substrate of monocarboxylate transporters (MCTs). Sodium-coupled monocarboxylate transporter 1 (SMCT1; SLC5A8) is expressed in kidney, thyroid gland, neurons, and intestinal tract and exhibits substrate specificity similar to that of the proton-dependent MCT (SLC16A) family. The role of SMCT1 in GHB disposition has not been determined. In this study we characterized the driving force, transport kinetics, and inhibitors of GHB uptake, as well as expression of SMCT and MCT isoforms, in rat thyroid follicular (

The ability to mount adaptive immune responses to vaccinations and viral infections declines with increasing age. To identify mechanisms leading to immunosenescence, primary CD4 T cell responses were examined in 60- to 75-year-old individuals lacking overt functional defects. Transcriptome analysis indicated a selective defect in zinc homeostasis. CD4 T cell activation was associated with zinc influx via the zinc transporter Zip6, leading to increased free cytoplasmic zinc and activation of negative feedback loops, including the induction of zinc-binding metallothioneins. In young adults, activation-induced cytoplasmic zinc concentrations declined after 2 days to below prestimulation levels. In contrast, activated naïve CD4 T cells from older individuals failed to downregulate cytoplasmic zinc, resulting in excessive induction of metallothioneins. Activation-induced metallothioneins regulated the redox state in activated T cells and accounted for an increased proliferation of old CD4 T cells, suggesting that regulation of T cell zinc homeostasis functions as a compensatory mechanism to preserve the replicative potential of naïve CD4 T cells with age.

IntroductionImmune homeostasis is tightly regulated by negative regulatory signals providing a counterbalance to activating stimuli. 1,2 Negative regulatory receptors have been described on all hematopoietic cells; a prime example that illustrates their importance is natural killer (NK) cell function. Self tolerance of NK cells is ensured by a set of inhibitory cell surface receptors that bind to self-major histocompatibility (MHC) class I ligands. 3 In humans, these receptors include the family of killer immunoglobulin-like receptors (KIRs).Inhibitory KIRs have long cytoplasmic tails with 2 immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Upon ligation of an inhibitory KIR, the ITIMs are phosphorylated and bind to the src homology 2 (SH2) domains of the phosphatase SHP-1. As a result of this binding, the catalytic site of SHP-1 is released from autoinhibition. 4 In NK cells, cognate binding of inhibitory KIRs to their human leukocyte antigen (HLA) ligands is enough to facilitate receptor clustering, ITIM phosphorylation, and SHP-1 activation. 5 The direct target of SHP-1 appears to be the guanine nucleotide exchange factor Vav1. 6 Dephosphorylation of Vav1 leads to inhibition of Rac1, 6 thereby preventing cytoskeletal rearrangement. One consequence is complete inhibition of NK cell activation. In fact, the formation of an activation platform between NK cells and target cells is completely prevented. 7 In addition to NK cells, KIRs are also expressed on T cells. 8,9 Naive and memory T cells are equipped to support their transcription; 10 however, expression is only found on senescent or enddifferentiated CD4 ϩ and CD8 ϩ T cells that have lost the expression of CD28. 11 The biologic function of inhibitory KIR expression on T cells is difficult to envision and likely different from NK cells. In NK cells, they are the basis for the missing self hypothesis 12 (ie, NK cells only respond to cells that have lost MHC class I expression). Otherwise, the inhibitory receptors keep NK cells completely unresponsive. Such a model would not be meaningful for T cells, the activation of which is dependent on MHC-restricted T-cell-receptor (TCR) triggering. Not surprisingly, functional studies of inhibitory receptors on T cells have come to conflicting results. 8,13,14 Inhibitory KIRs on selected tumor-specific CD8 ϩ T cells in patients with melanoma 15 and renal carcinoma were shown to inhibit tyrosine phosphorylation of early signaling proteins, lipid rafts, TCR/CD3 clustering, and the reorganization of the actin cytoskeleton; they also completely shut down T-cell activation. Consequently, the tumor-specific immune response was dampened, supporting a model of KIR expression on T cells as a cause of defective immunosurveillance. 8 Other studies of inhibitory receptors, such as immunoglobulin-like transcript 2 (ILT-2) on human CD8 T cells and GP49B1 on murine CD8 T cells, have only G.H. designed research, performed research, analyzed data, and wrote the paper; K.S. performed research and analyzed data; D.C. performed rese...