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Previous study has demonstrated that melatonin plays a critical role in monochromatic-light-induced lymphocyte proliferation in response to T cell mitogen concanavalin A (ConA). However, its intracellular mechanism is still unclear. In this study, we investigate the intracellular signal pathways of melatonin receptor-mediated T-lymphocyte proliferation in the spleens of chicks exposed to different light wavelengths. Results showed that green light enhanced T-lymphocyte proliferation by 2.46–6.83% and increased splenic mRNA and protein expressions of melatonin receptor subtypes (Mel1a, Mel1b and Mel1c) by 16.05–40.43% compared with the white, red and blue light groups. However, pinealectomy resulted in a decrease in T-lymphocyte proliferation and melatonin receptor expression with no statistically significant differences between the different light groups. In vitro experiments showed that the Mel1b selective antagonist 4P–PDOT, the Mel1c selective antagonist prazosin and the mitogen-activated protein kinase kinase-1 (MEK-1) inhibitor PD98059 suppressed both melatonin-induced lymphocyte proliferation in response to ConA and melatonin- and ConA-stimulated extracellular signal-regulated kinase 1/2 (ERK1/2) activity but that the Mel1a/Mel1b non-selective antagonist luzindole did not. In addition, pretreatment with forskolin (FSK, the adenylyl cyclase activator), H89 (the PKA inhibitor), U73122 (the PLC inhibitor) or Go6983 (the broad spectrum PKC inhibitor) markedly attenuated melatonin- and ConA-stimulated T-lymphocyte proliferation and ERK1/2 activity. These results demonstrate that melatonin mediates green-light-induced T-lymphocyte proliferation via the Mel1b and Mel1c receptors by triggering crosstalk between the cAMP/PKA and PLC/PKC signal pathways followed by ERK1/2 activation.

The present study was performed on antigen-presenting cells (APCs) of Theileria annulata transformed dendritic cells (TaDCs) and monocyte-derived dendritic cells (MoDCs) to compare differences in antigen presentation and stimulation of T lymphocyte proliferation. Antigen presentation for T lymphocyte proliferation was analysed by flow cytometry. Additionally, the level of mRNA transcription of small GTPases of the Rab family expressed in the TaDC cell line was analysed by quantitative real-time polymerase chain reaction (Q-RT-PCR). The endocytosis rate of TaDCs was significantly ( P < 0.01) lower than in MoDCs. In contrast, when T lymphocytes were co-cultured with TaDC-APCs T cell proliferation was similar, while co-culture with MoDC-APC stimulated proliferation of CD4 + cells to a greater degree than CD8 + cells. However, the efficacy of TaDC-APCs to stimulate T lymphocytes dropped as the number of passages of TaDC-APC increased. Likewise, the transcription level of Rab family genes also significantly ( P > 0.001) declined with progressive passages (>50) of the TaDC cell line. We conclude that initially the TaDC cell line efficiently presents antigen to stimulate T lymphocyte proliferation to produce a cellular immune response against the presented antigen.

Our current investigation was aimed to study differential influence of heat stress on defensive functions of blood polymorphonuclear cells among native and crossbred cows by culturing them in vitro after animal exposure to in vivo heat stress. Blood was collected from 18 cows which were divided in to three groups based on their breed as, group I (Sahiwal), group II (Tharparkar) and group III (Crossbred). THI was calculated by temperature and relative humidity (RH). PMN were isolated and were incubated at 38°C. Phagocytosis and lymphocyte proliferation was then investigated by NBT and MTT assays, respectively. The overall mean THI was significantly (p < 0.5) higher during summer (88.41 ± 1.54) when compared to the winter season (64.75 ± 0.97). There is a significant high lymphocytic proliferation in Group II when compared to Group III cattle. Also, there is a significant decrease in PA during the summer when compared to winter in all the breeds and in group III there is significant decrease in LPA during summer. The results of the present study suggest that indigenous cattle Tharparkar exhibited more tolerance to heat stress than the Group-I and Group-III during summer. However, in winter, all the breeds showed similar.

We investigated the effects of polysaccharide extracts from 2 mushrooms, Lentinus edodes (LenE) and Tremella fuciformis (TreE), and an herb, Astragalus membranaceus (AstE), on cellular and humoral immune responses of Eimeria tenella-infected chickens. A total of 150 broiler chicks were assigned to 5 treatment groups: 3 groups were infected with E. tenella and fed with extracts (LenE, TreE, and AstE), and 2 control groups were infected with or without E. tenella. The 3 extracts were given at the level of 1 g/kg of the diet from 8 to 14 d of age. Specific systemic and cecum mucosal antibody production, proliferation of splenocytes, and peripheral T and B lymphocytes were measured during the 3 wk following Eimeria infection. A significantly higher production of specific IgA, IgM (at d 14 and 21 postinfection), and IgG (at d 21 postinfection) were detected in the Eimeria-infected groups fed with the extracts than in the infected group not fed with the extracts. Of the 3 extracts, TreE stimulated a slightly higher production of specific IgM (P = 0.052), and a significantly higher IgG production at 21 d postinfection. The cecal antibody production showed a similar trend to that of serum antibodies. The overall mean levels of cecal-specific IgA and IgG of the groups fed with extracts were significantly higher at 14 and 21 d postinfection compared with the group not fed with extracts. Of the 3 extracts, the AstE-fed group showed the highest IgG production at d 7 postinfection. Both TreE- and LenE-fed groups had significantly higher IgM and IgG levels compared with the AstE group at d 21 postinfection. The extract-fed groups also showed a significantly higher antigen-specific proliferation of splenocytes at 14 and 21 d postinfection compared with the group not fed with the extracts. The overall mean of erythrocyte rosette-forming cells (ERFC %) (at d 14 and 21) and erythrocyte-antibody-complement cells (EAC %) (at d 14) of the groups fed with the extracts was significantly higher compared with the group not fed the extracts. It is concluded from this study that supplementation with mushroom and herb extracts resulted in enhancement of both cellular and humoral immune responses in E. tenella-infected chickens.

Some rare HIV-1-infected individuals, referred to as HIV controllers (HIC), have persistently undetectable plasma viral load in the absence of therapy. This control of HIV-1 replication has been associated with a strong, multifunctional specific CD8⁺ T cell response. However, no direct link between this immune response and the control of viremia has so far been provided. We investigated parameters of specific CD8⁺ T cell response and in vitro susceptibility to HIV-1 infection in 11 HIC. We found high frequencies of HIV-specific CD8⁺ T cells. Interestingly, these cells expressed the activation marker HLA-DR but not CD38. This unique phenotype differentiates HIV-specific CD8⁺ T cells from HIC and noncontroller subjects and likely reflects a high potential to expand upon exposure to antigen and a capacity to exert effector functions. Accordingly, although CD4⁺ T cells from HIC were fully susceptible to HIV-1 superinfection, their CD8⁺ T cells effectively suppressed HIV-1 infection. Remarkably, this potent anti-HIV activity was observed without prior stimulation of CD8⁺ T cells. This activity was not mediated by secreted inhibitory factors but was due to the elimination of infected CD4⁺ T cells and was observed only with autologous CD4⁺ T cells, indicating an HLA-restricted cytotoxic mechanism. This constitutive antiviral capacity of CD8⁺ T cells could account for the control of viral replication in HIC.

Glutamine is the most abundant and versatile amino acid in the body. In health and disease, the rate of glutamine consumption by immune cells is similar or greater than glucose. For instance, in vitro and in vivo studies have determined that glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities, and neutrophil bacterial killing. Glutamine release to the circulation and availability is mainly controlled by key metabolic organs, such as the gut, liver, and skeletal muscles. During catabolic/hypercatabolic situations glutamine can become essential for metabolic function, but its availability may be compromised due to the impairment of homeostasis in the inter-tissue metabolism of amino acids. For this reason, glutamine is currently part of clinical nutrition supplementation protocols and/or recommended for immune suppressed individuals. However, in a wide range of catabolic/hypercatabolic situations (e.g., ill/critically ill, post-trauma, sepsis, exhausted athletes), it is currently difficult to determine whether glutamine supplementation (oral/enteral or parenteral) should be recommended based on the amino acid plasma/bloodstream concentration (also known as glutaminemia). Although the beneficial immune-based effects of glutamine supplementation are already established, many questions and evidence for positive in vivo outcomes still remain to be presented. Therefore, this paper provides an integrated review of how glutamine metabolism in key organs is important to cells of the immune system. We also discuss glutamine metabolism and action, and important issues related to the effects of glutamine supplementation in catabolic situations.

This study assessed the effect of micronutrient supplementation around peripartum period on immune function, reproductive performance, milk yield and milk quality of crossbred cows. Thirty pregnant crossbred cows in their late gestation were selected and randomly divided into five groups for study. Six cows in each group were supplemented with vitamin E (VE) (2000 IU/cow/day), vitamin A (VA) (100,000 IU/cow/day), copper (Cu) (20 ppm/cow/day), zinc (Zn) (80 ppm/cow/day) individually from 45 days pre-calving to 45 days post-calving and one group without any supplementation served as control. Immune function was studied by in vitro phagocytic activity (PA) of blood neutrophils, lymphocyte proliferation response (LPR) and plasma interleukin-8 (IL-8) concentration. Supplementation of VA significantly (P < 0.05) increased the in vitro PA of blood neutrophils and decreased milk somatic cell counts (SCC). Zn supplementation significantly (P < 0.05) increased the T lymphocyte proliferation response, whereas B lymphocyte LPR was significantly (P < 0.05) increased with both VA and Zn supplementation as compared to the control cows. Plasma IL-8 concentration was significantly (P < 0.05) higher in all supplemented cows. Supplementation of VE, VA and Zn significantly (P < 0.05) reduces days open, whereas VA significantly (P < 0.05) reduced the service per conception. In this study, it is concluded that VE, VA and Zn supplementation around peripartum period can boost the immunity and improve the reproductive performance of crossbred cows in a semi-arid tropical environment.

The protease activity of the paracaspase Malt1 contributes to antigen receptor-mediated lymphocyte activation and lymphomagenesis. Malt1 activity is required for optimal NF-κB activation, but little is known about the responsible substrate(s). Here we report that Malt1 cleaved the NF-κB family member RelB after Arg-85. RelB cleavage induced its proteasomal degradation and specifically controlled DNA binding of RelA- or c-Rel–containing NF-κB complexes. Overexpression of RelB inhibited expression of canonical NF-κB target genes and led to impaired survival of diffuse large B-cell lymphoma cell lines characterized by constitutive Malt1 activity. These findings identify a central role for Malt1-dependent RelB cleavage in canonical NF-κB activation and thereby provide a rationale for the targeting of Malt1 in immunomodulation and cancer treatment.

Background DiGeorge Syndrome (DGS), a microdeletion syndrome, shows a broad spectrum from mild T-cell lymphopenia to severe combined immunodeficiency. Aim To define the clinical/immunophenotypical biomarkers for DGS. Patients and Methods A total of 72 patients with 22q11.2 deletion( n  = 66) and those fulfilling the DGS criteria without deletion ( n  = 6) were enrolled. Results The male/female ratio was 41/31. Median age at clinical diagnosis was 1.7 years (0 days-22 years) with follow-up for 21.7 months (0 days-17.3 years). Common evaluation reasons were cardiac features (30.6%), failure to thrive (15.3%), and neurological features (15.3%). Craniofacial dysmorphism (64/66, 97%), central nervous system findings (62/72, 86.1%), and congenital cardiovascular defect (43/70, 61.4%) were common. We noted lymphopenia (30/72, 41.7%) and low IgM (25/69, 36.2%). T helper cell counts were low in 49.3% (33/67). T cytotoxic and NK cell counts were normal/high in 80.6% (54/67) and 97% (65/67) of patients, respectively. 42.3% (11/26) had low CD4 + TEMRA, and 34.6% (9/26) had low CD8 + TEM percentages. None had low CD8 + TEMRA. B cells were normal/high (52/67, 77.6%). 30.8%(8/26) had low switched-memory and 38.5% (10/26) had low active B cell percentages. Low IgA levels were associated with decreased lymphocyte activation and recent thymic emigrant (RTE) cell percentages. Six(8.3%) patients with lymphopenia, three of whom had congenital athymia, died. Conclusion CD4 lymphopenia was more common than CD8 lymphopenia. Normal/high CD8 + and NK cell counts were remarkable. Increased CD8+ TEMRA cells seem to indicate peripheral homeostatic proliferation following viral infections. Low serum IgA correlated with low RTE% and impaired T-cell function. DGS severity markers include hypocalcemia, congenital cardiac anomaly, and T-cell lymphopenia. Graphical Abstract

Reestablishing self-tolerance in autoimmunity is thought to depend on self-reactive regulatory T cells (Tregs). Exploiting these antigen-specific regulators is hampered by the obscure nature of disease-relevant autoantigens. We have uncovered potent disease-suppressive Tregs recognizing Heat Shock Protein (Hsp) 70 self-antigens, enabling selective activity in inflamed tissues. Hsp70 is a major contributor to the MHC class II ligandome. Here we show that a conserved Hsp70 epitope (B29) is present in murine MHC class II and that upon transfer, B29-induced CD4 ⁺CD25 ⁺Foxp3 ⁺ T cells suppress established proteoglycan-induced arthritis in mice. These self-antigen–specific Tregs were activated in vivo, and when using Lymphocyte Activation Gene-3 as a selection marker, as few as 4,000 cells sufficed. Furthermore, depletion of transferred Tregs abrogated disease suppression. Transferred cells exhibited a stable phenotype and were found in joints and draining lymph nodes up to 2 mo after transfer. Given that (i) B29 administration by itself suppressed disease, (ii) our findings were made with wild-type (T-cell receptor nontransgenic) Tregs, and (iii) the B29 human homolog is presented by HLA class II, we are nearing translation of antigen-specific Treg activation as a promising intervention for chronic inflammatory diseases.