Naive Helper Research Articles

T Cell Development and Function.

T cells play critical roles in the immune system, including in responses to cancer, autoimmunity, and tissue regeneration. T cells arise from common lymphoid progenitors (CLPs) that differentiate from hematopoietic stem cells in the bone marrow. CLPs then traffic to the thymus, where they undergo thymopoiesis through a number of selection steps, resulting in mature single positive naive CD4 helper or CD8 cytotoxic T cells. Naive T cells are home to secondary lymphoid organs like lymph nodes and are primed by antigen-presenting cells, which scavenge for both foreign and self-antigens. Effector T cell function is multifaceted, including direct target cell lysis and secretion of cytokines, which regulate the functions of other immune cells (refer to "Graphical Abstract"). This review will discuss T cell development and function, from the development of lymphoid progenitors in the bone marrow to principles that govern T cell effector function and dysfunction, specifically within the context of cancer.

Lymphocyte Subsets in Defense Against New Pathogens in Patients with Cancer.

Immunity in cancer patients is modified both by the cancer itself and by oncospecific treatments. Whether a patient's adaptive immunity is impaired depends on their levels of naive lymphocytes and other cell populations. During the COVID-19 pandemic, cancer patients are at greater risk of progressing to severe forms of the disease and have higher mortality rates than individuals without cancer, particularly while they are receiving cancer-specific therapies. An individual's protection against infection, their response to vaccines, and even the tests that determine the humoral immune response to SARS-CoV-2, depend on lymphocyte populations, meriting their study. Estimate blood concentrations of lymphocytes involved in the immune response to new pathogens in cancer patients. We carried out an analytical study of 218 cancer patients; 124 women and 94 men, 26-93 years of age, who were treated at the National Oncology and Radiobiology Institute in Havana, Cuba, March-June, 2020. Patients were divided into five groups: (1) those with controlled disease who were not undergoing cancer-specific treatment; (2) those undergoing debulking surgery; (3) patients undergoing chemotherapy; (4) patients undergoing radiation therapy and (5) patients currently battling infection. We evaluated the following peripheral blood lymphocyte subpopulations via flow cytometry: B lymphocytes (total, naive, transitional, memory, plasmablasts and plasma cells); T lymphocytes (total, helper, cytotoxic and their respective naive, activated, central memory and effector memory subsets); and total, secretory and cytotoxic natural killer cells and T natural killer cells. We also estimated neutrophil/lymphocyte ratios. Lymphocyte concentrations were associated with controlled disease and standard cancer therapy. For variables that did not fall within a normal distribution, ranges were set by medians and 2.5-97.5 percentiles. The two-tailed Mann-Whitney U test was used to measure the effect of sex and to compare lymphocyte populations. We calculated odds ratios to estimate lymphopenia risk. All cancer patients had lower values of naive helper and cytotoxic T lymphocyte populations, naive B lymphocytes, and natural killer cells than normal reference medians. Naive helper T cells were the most affected subpopulation. Memory B cells, plasmablasts, plasma cells, activated T helper cells, and cytotoxic central memory T cells were increased. Patients undergoing treatment had lower levels of naive lymphocytes than untreated patients, particularly during radiation therapy. The risk of B lymphopenia was higher in patients in treatment. The odds ratio for B lymphopenia was 8.0 in patients who underwent surgery, 12.9 in those undergoing chemotherapy, and 13.9 in patients in radiotherapy. Cancer and conventional cancer therapies significantly affect peripheral blood B lymphocyte levels, particularly transitional T helper lymphocytes, reducing the immune system's ability to trigger primary immune responses against new antigens.

Twin study reveals non-heritable immune perturbations in multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system underpinned by partially understood genetic risk factors and environmental triggers and their undefined interactions1,2. Here we investigated the peripheral immune signatures of 61 monozygotic twin pairs discordant for MS to dissect the influence of genetic predisposition and environmental factors. Using complementary multimodal high-throughput and high-dimensional single-cell technologies in conjunction with data-driven computational tools, we identified an inflammatory shift in a monocyte cluster of twins with MS, coupled with the emergence of a population of IL-2 hyper-responsive transitional naive helper T cells as MS-related immune alterations. By integrating data on the immune profiles of healthy monozygotic and dizygotic twin pairs, we estimated the variance in CD25 expression by helper T cells displaying a naive phenotype to be largely driven by genetic and shared early environmental influences. Nonetheless, the expanding helper T cells of twins with MS, which were also elevated in non-twin patients with MS, emerged independent of the individual genetic makeup. These cells expressed central nervous system-homing receptors, exhibited a dysregulated CD25–IL-2 axis, and their proliferative capacity positively correlated with MS severity. Together, our matched-pair analysis of the extended twin approach allowed us to discern genetically and environmentally determined features of an MS-associated immune signature.

IL4Rα and IL13Rα1 Are Involved in the Development of Human Gallbladder Cancer.

Background: Gallbladder cancer is commonly associated with inflammation, which indicates that inflammation-related cytokines and cytokine receptors are related to the progression of gallbladder cancers. Interleukin 4 (IL4) is a well-known cytokine that promotes the differentiation of naive helper T cells (Th0) to T helper type 2 cells (Th2). IL13 is a cytokine that is secreted by Th2 cells. IL4 and IL13 are closely related in immune responses. However, the role of IL4Rα and IL13Rα1 signaling pathway has not been fully understood in the development of gallbladder cancer. Methods: In human gallbladder carcinomas, the expression of IL4Rα and IL13Rα1 were evaluated with immunohistochemical staining in tissue microarray tissue sections. After knockdown of IL4Rα or IL13Rα1, cell assays to measure the proliferation and apoptosis and Western blotting analysis were conducted in SNU308 human gallbladder cancer cells. Since Janus kinases2 (JAK2) was considered as one of the down-stream kinases under IL4Rα and IL13Rα1 complex, the same kinds of experiments were performed in SNU308 cells treated with AZD1480, Janus-associated kinases2 (JAK2) inhibitor, to demonstrate the cytotoxic effect of AZD1480 in SNU308 cells. Results: Immunohistochemical expression of IL4Rα was significantly associated with the expression of IL13Rα1 in human carcinoma tissue. In univariate analysis, nuclear expression of IL4Rα, cytoplasmic expression of IL4Rα, nuclear expression of IL13Rα1, and cytoplasmic expression of IL13Rα1 were significantly associated with shorter overall survival and shorter relapse-free survival. Multivariate analysis revealed nuclear expression of IL4Rα as an independent poor prognostic indicator of overall survival and relapse-free survival. Then, we found that knockdown of IL4Rα or IL13Rα1 decreased viability and induced apoptosis in SNU308 cells via activation of FOXO3 and similarly, AZD1480 decreased viability and induced apoptosis in SNU308 cells with dose dependent manner. Conclusions: Taken together, our results suggest that IL4Rα and IL13Rα1 might be involved in the development of human gallbladder cancer cells and IL4Rα and IL13Rα1 complex/JAK2 signaling pathway could be efficient therapeutic targets for gallbladder cancer treatment.

Melanoma Cell Adhesion Molecule Expressing Helper T Cells in CNS Inflammatory Demyelinating Diseases.

Background and ObjectiveTo elucidate the relationship between melanoma cell adhesion molecule (MCAM)-expressing lymphocytes and pathogenesis of CNS inflammatory demyelinating diseases (IDDs).MethodsPatients with multiple sclerosis (MS) (n = 72) and neuromyelitis optica spectrum disorder (NMOSD, n = 29) were included. We analyzed the frequency and absolute numbers of MCAM+ lymphocytes (memory helper T [mTh] cells, naive helper T cells, CD8+ T cells, and B cells) in the peripheral blood (PB) and the CSF of patients with MS and NMOSD, treated with/without disease-modifying drugs (DMDs) or steroids, using flow cytometry.ResultsThe frequency of MCAM+ cells was higher in the mTh cell subset than that in other lymphocyte subsets. A significant increase in the frequency and the absolute number of MCAM+ mTh cells was observed in the PB of patients with NMOSD, whereas no increase was observed in the PB of patients with MS. The frequency of CSF MCAM+ mTh cells was higher in relapsing patients with MS and NMOSD than that in the control group. Although there was no difference in the frequencies of MCAM+ lymphocytes among the DMD-treated groups, fingolimod decreased the absolute number of MCAM+ lymphocytes.DiscussionMCAM+ mTh cells were elevated in the CSF of relapsing patients with MS and in both the PB and CSF of patients with NMOSD. These results indicate that MCAM contributes to the pathogenesis of MS and NMOSD through different mechanisms. MCAM could be a therapeutic target of CNS IDDs, and further study is needed to elucidate the underlying mechanism of MCAM in CNS IDD pathogenesis.

"Age Related Differences in the Biology of Chronic Graft-Versus-Host Disease After Hematopoietic Stem Cell Transplantation".

It is established that pediatric hematopoietic stem cell transplant (HSCT) recipients have a lower rate of chronic graft-versus-host disease (cGvHD) compared to adults. Our group has previously published immune profiles changes associated with cGvHD of clinically well-defined adult and pediatric HSCT cohorts. Since all analyses were performed by the same research group and analyzed using identical methodology, we first compared our previous immune profile analyses between adults and children. We then performed additional analyses comparing the T cell populations across age groups, and a sub-analysis of the impact of the estimated pubertal status at time of HSCT in our pediatric cohort. In all analyses, we corrected for clinical covariates including total body irradiation and time of onset of cGvHD. Three consistent findings were seen in both children and adults, including elevations of ST2 and naive helper T (Th) cells and depression of NKreg cells. However, significant differences exist between children and adults in certain cytokines, B cell, and Treg populations. In children, we saw a broad suppression of newly formed B (NF-B) cells, whereas adults exhibited an increase in T1-CD21lo B cells and a decrease in T1-CD24hiCD38hi B cells. Prepubertal children had elevations of aminopeptidase N (sCD13) and ICAM-1. Treg abnormalities in children appeared to be primarily in memory Treg cells, whereas in adults the abnormalities were in naïve Treg cells. In adults, the loss of PD1 expression in naïve Treg and naïve Th cells was associated with cGvHD. We discuss the possible mechanisms for these age-related differences, and how they might theoretically impact on different therapeutic approaches to cGvHD between children and adults.

Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies

AbstractHuman graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1− and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.

Differentiation Paths of Peyer’s Patch LysoDCs Are Linked to Sampling Site Positioning, Migration, and T Cell Priming

The monocyte-derived phagocytes termed LysoDCs are hallmarks of Peyer's patches, where their main function is to sample intestinal microorganisms. Here, we study their differentiation pathways in relation with their sampling, migratory, and Tcell-priming abilities. Among four identified LysoDC differentiation stages displaying similar phagocytic activity, one is located in follicles, and the others reside in subepithelial domes (SED), where they proliferate and mature as they get closer to the epithelium. Mature LysoDCs but not macrophages express a gene set in common with conventional dendritic cells and prime naive helper Tcells invitro. At steady state, they do not migrate into naive Tcell-enriched interfollicular regions (IFRs), but upon stimulation, they express the chemokine receptor CCR7 and migrate from SED to the IFR periphery, where they strongly interact with proliferative immune cells. Finally, we show that LysoDCs populate human Peyer's patches, strengthening their interest as targets for modulating intestinal immunity.

Immunomodulating effects of alpha-fetoprotein

Alpha-fetoprotein (AFP), synthesized by embryonic tissues, enters the bloodstream of a mother performing both transport and immunomodulating functions. The aim of the work is to assess the effect of AFP on the differentiation of regulatory (Treg and Th17) and effector (TEM, TEMRA) subpopulations in vitro. For this, isolated cultures of T-helper cells were incubated with physiological concentrations of the native AFP preparation (10, 50, 100 IU/ml). In our experimental model, no apparent effects of AFP on Treg/Th17 differentiation were revealed. However, it was found out that AFP impeded the conversion of naive helper T cells into TEM and TEMRA, while simultaneously reducing the total production of IL-4 and IFN-y cytokines by these cells. The next task is to study the role of AFP in the regulation of differentiation and functions of myeloid suppressor cells (MDSC). Understanding these processes will expand our vision of the role of AFP in the formation of fetomaternal tolerance, as well as to formulate a new concept of its action as a pharmacological drug.

Anti-Thymocyte Globulin Prophylaxis Induces a Decrease in Naive Th Cells to Inhibit the Onset of Chronic Graft-versus-Host Disease: Results from the Canadian Bone Marrow Transplant Group (CBMTG) 0801 Study.

Anti-thymocyte globulin (ATG) is an established approach to decrease chronic GVHD (cGVHD), yet the exact mechanism is uncertain. To better understand the mechanism of action of ATG in preventing cGVHD, we evaluated the day 100 immune reconstitution of known cGVHD cellular biomarkers using patients from the randomized Canadian Bone Marrow Transplant Group (CBMTG) 0801 trial, which demonstrated a significant impact of ATG on cGVHD. In a separate companion biology study, we evaluated the impact of ATG prophylaxis on cGVHD cellular markers at day 100 in 40 CBMTG 0801 patients. Analysis focused on previously identified cGVHD cellular biomarkers, including naive helper T (Th) cells, recent thymic emigrant (RTE) Th cells, CD21low B cells, CD56bright NKreg cells, and Treg cells ST2, osteopontin, soluble B-cell activating factor (sBAFF), Interleukin-2 receptor alpha (sCD25), T-cell immunoglobulin and mucin domain-3 (TIM-3), matrix metallopeptidase 3, ICAM-1, C-X-C motif chemokine 10 (CXCL10), and soluble aminopeptidase N. The ATG-treated group had a >10-fold decrease in both RTE naive Th and naive Th cells (P < .0001) and a 10-fold increase in CD56bright NKreg cells (P < .0001). Treg cells, conventional Th cells, CD21low B cells, and all plasma markers were not affected. In the populations most affected by ATG, changes in naive Th cells were associated with the later development of cGVHD. This analysis suggests that ATG primarily impacts on cGVHD through suppression of naive Th cell expansion after transplantation. These associations need to be validated in additional studies.

When Can Intelligent Helper Node Selection Improve the Performance of Distributed Storage Networks?

The concept of distributed storage networks (DSNs) mostly follows two main modeling assumptions: Any $k$ out of $n$ surviving nodes should be able to reconstruct the protected file; and if one node fails, the replacement node can access $d$ helper nodes to repair its content either functionally or exactly. Two major existing approaches for DSNs are the so-called regenerating codes (RCs) and locally repairable codes (LRCs), which have different design philosophies and focus on distinct applications. Instead of being limited by the framework of either RCs or LRCs, this work answers a fundamental question for general DSNs: For an arbitrarily given $(n,k,d)$ value, whether there exists an intelligent helper node selection design that can strictly improve the storage-bandwidth tradeoff when compared with naive blind helper selection. Surprisingly, the answer is negative for a large set of $(n,k,d)$ values. Namely, for those $(n,k,d)$ values even the best helper selection design offers no gain over a blind solution. We call those $(n,k,d)$ values indifferent-to-helper-selection (ITHS). The main contribution of this work is a necessary and sufficient condition that characterizes whether an $(n,k,d)$ value is ITHS. As a fundamental study, this work assumes functional repair with unlimited computing power for encoding/decoding and focuses on the fundamental performance limits of intelligent helper selection. A new helper selection scheme, termed family helper selection , is proposed and used in the achievability analysis. For some scenarios, the proposed scheme is indeed optimal (as good as any helper selection one can design).

P21-activated kinase 2 is essential in maintenance of peripheral Foxp3+ regulatory T cells.

SummaryThe p21‐activated kinase 2 (Pak2), an effector molecule of the Rho family GTPases Rac and Cdc42, regulates diverse functions of T cells. Previously, we showed that Pak2 is required for development and maturation of T cells in the thymus, including thymus‐derived regulatory T (Treg) cells. However, whether Pak2 is required for the functions of various subsets of peripheral T cells, such as naive CD4 and helper T‐cell subsets including Foxp3+ Treg cells, is unknown. To determine the role of Pak2 in CD4 T cells in the periphery, we generated inducible Pak2 knockout (KO) mice, in which Pak2 was deleted in CD4 T cells acutely by administration of tamoxifen. Temporal deletion of Pak2 greatly reduced the number of Foxp3+ Treg cells, while minimally affecting the homeostasis of naive CD4 T cells. Pak2 was required for proliferation and Foxp3 expression of Foxp3+ Treg cells upon T‐cell receptor and interleukin‐2 stimulation, differentiation of in vitro induced Treg cells, and activation of naive CD4 T cells. Together, Pak2 is essential in maintaining the peripheral Treg cell pool by providing proliferation and maintenance signals to Foxp3+ Treg cells.

Modeling Macrophage Polarization and Its Effect on Cancer Treatment Success.

Positive feedback loops drive immune cell polarization toward a pro-tumor phenotype that accentuates immunosuppression and tumor angiogenesis. This phenotypic switch leads to the escape of cancer cells from immune destruction. These positive feedback loops are generated by cytokines such as TGF-β, Interleukin-10 and Interleukin-4, which are responsible for the polarization of monocytes and M1 macrophages into pro-tumor M2 macrophages, and the polarization of naive helper T cells intopro-tumor Th2 cells. In this article, we present a deterministic ordinary differential equation (ODE) model that includes key cellular interactions and cytokine signaling pathways that lead to immune cell polarization in the tumor microenvironment. The model was used to simulate various cancer treatments in silico. We identified combination therapies that consist of M1 macrophages or Th1 helper cells, coupled with an anti-angiogenic treatment, that are robust with respect to immune response strength, initial tumor size and treatment resistance. We also identified IL-4 and IL-10 as the targets that should be neutralized in order to make these combination treatments robust with respect to immune cell polarization. The model simulations confirmed a hypothesis based on published experimental evidence that a polarization into the M1 and Th1 phenotypes to increase the M1-to-M2 and Th1-to-Th2 ratios plays a significant role in treatment success. Our results highlight the importance of immune cell reprogramming as a viable strategy to eradicate a highly vascularized tumor when the strength of the immune response is characteristically weak and cell polarization to the pro-tumor phenotype has occurred.

THE VALUE OF EXTRACORPOREAL PHOTOCHEMOTHERAPY IN RENAL TRANSPLANT REJECTION INHIBITION

The aim of the study was to determine the value of extracorporeal photochemotherapy (EPCT) in the induction of tissue tolerance in renal transplantation. EPCT was applied to 24 renal transplant recipients in early postoperative period, the control group consisted of paired transplant recipients. In the group using EPCT over a three-year period of observation no clinical or histological signs of rejection were observed. In the control group, histologically confirmed rejection was observed in 4 cases, in 2 cases transplantectomy due to acute rejection. The reducing incidence of infectious complications in the study group compared with the control one (4 and 19 cases, respectively) and decreasing number of hospitalizations on various reasons (8 and 47 cases in the study and control groups, respectively) were also noted. Three-year graft survival was 100% and 83.3% in the study and the control groups, respectively. Using immunological tests in 30 days after transplantation the stable number of cells expressing coactivation molecules (57.7 ± 18.2 and 52.7 ± 23.2%, respectively, p &gt; 0.05) and the density of their co-expression (22.7 ± 6.0 and 19.6 ± 7.0 units, respectively, p &gt; 0.05) were demonstrated, while in the study group, the pronounced and statistically significant reduction both in the amount of cells expressing co-activation receptors (from 57.7 ± 18.2 to 34.5 ± 11.4%, p &lt; 0.05) and in the density of these receptors on naive helper T-lymphocytes (from 22.7 ± 6.0 to 16.8 ± 5.1 units, p &lt; 0.05) was revealed. Thus, it is noted that EPCT provides induction of tolerance to MHC antigens in kidney transplantation due to reducing expression of coactivation molecules which promote the second signaling pathway to T-cell receptor activation.

Surface expression of trout CD4-1 and CD4-2 defines novel populations of functionally distinct CD4+ T cells in teleost fish

The largest subset of T cells in jawed vertebrates express a TCR bearing α and β chains that recognize antigens bound to MHC molecules. Such T cells use two main co-receptors, CD4 and CD8 which show mutually exclusive expression on naive helper T (Th) and cytotoxic T cells respectively. Tetrapods contain a single CD4 co-receptor with four immunoglobulin domains that likely arose from a primordial two-domain ancestor. Notably, teleost fish contain two CD4 genes. Like tetrapod CD4, CD4-1 of rainbow trout includes four-immunoglobulin domains while CD4-2 contains only two. Thus far the concurrent surface expression of CD4-1 and CD4-2 on teleost leukocytes has not been determined due to the lack of reagents capable of detecting both molecules in a single species. In the absence of those, transcript levels have been used to assess expression patterns of CD4-1 and CD4-2, but results in different teleost species have been inconclusive. Hence, very little is known regarding the existence of different teleost CD4 T cells subsets and their roles in immunity. Here we generated monoclonal antibodies against trout CD4-1 and CD4-2 that enabled the identification of two bona fide CD4 T-cell populations, a predominant lymphocyte population co-expressing surface CD4-1 and CD4-2 (CD4 DP) and a minor subset expressing only CD4-2 (CD4-2 SP). While both subsets produced equivalent levels of Th1, Th17, and Treg cytokines in response to Yersinia ruckeri infection, CD4-2 SP lymphocytes were less proliferative to PHA and alloantigen stimulations and displayed a more restricted TCRβ repertoire. These data suggest that CD4-2 SP cells represent a functionally distinct population and may embody a vestigial CD4 T cell subset, the roles of which reflect those of primeval CD4 T cells. In addition, significant disparities in their transcriptomes as well as in their abundance in systemic and mucosal organs indicate further functional differences between CD4 DP and CD4-2 SP subsets. This study fills in an important gap in the knowledge of teleost CD4-bearing lymphocytes thus revealing critical insights into their functional roles and evolutionary origins. Importantly, as our knowledge on CD4 T-cell responses in teleosts is very scarce, our findings will be critical for the design of more effective vaccines for fish that induce strong effector and memory CD4 T cell responses.

MALT1 is an intrinsic regulator of regulatory T cells

Regulatory T cells (Tregs) are crucial for the maintenance of immunological self-tolerance and their absence or dysfunction can lead to autoimmunity. However, the molecular pathways that govern Treg biology remain obscure. In this study, we show that the nuclear factor-κB signalling mediator mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an important novel regulator of both Tregs originating in the thymus (‘natural’ or nTregs) and Tregs induced to differentiate from naive thymocyte helper (Th) cells in the periphery (‘induced’ or iTregs). Our examination of mice deficient for MALT1 revealed that these mutants have a reduced number of total Tregs. In young Malt1−/− mice, nTregs are totally absent and iTreg are diminished in the periphery. Interestingly, total Treg numbers increase in older Malt1−/− mice as well as in Malt1−/− mice subjected to experimentally induced inflammation. iTregs isolated from WT and Malt1−/− mice were indistinguishable with respect to their ability to suppress the activities of effector T cells, but Malt1−/− iTregs expressed higher levels of Toll-like receptor (TLR) 2. Treatment of WT and Malt1−/− Th cells in vitro with the TLR2 ligand Pam3Cys strongly enhanced the induction and proliferation of Malt1−/− iTregs. Our data suggest that MALT1 supports nTreg development in the thymus but suppresses iTreg induction in the periphery during inflammation. Our data position MALT1 as a key molecule that contributes to immune tolerance at steady-state while facilitating immune reactivity under stress conditions.

Innate and adaptive immune functions of peyer's patch monocyte-derived cells.

Peyer's patches (PPs) are primary inductive sites of mucosal immunity. Defining PP mononuclear phagocyte system (MPS) is thus crucial to understand the initiation of mucosal immune response. We provide a comprehensive analysis of the phenotype, distribution, ontogeny, lifespan, function, and transcriptional profile of PP MPS. We show that monocytes give rise to macrophages and to lysozyme-expressing dendritic cells (LysoDCs), which are both involved in particulate antigen uptake, display strong innate antiviral and antibacterial gene signatures, and, upon TLR7 stimulation, secrete IL-6 and TNF, but neither IL-10 nor IFNγ. However, unlike macrophages, LysoDCs display a rapid renewal rate, strongly express genes of the MHCII presentation pathway, and prime naive helper T cells for IFNγ production. Our results show that monocytes differentiate locally into LysoDCs and macrophages, which display distinct features from their adjacent villus counterparts.

Study of Immune Effector Cells in Leukoplakia and Oral Cancer

Aim: Immunosuppresion in oral squamous cell carcinoma (OSCC) is related to high degree of recurrence and believed to develop from premalignant lesion. Leukocytes especially T cell subsets are important in immune surveillance during malignant transformation. This study has been planned to observe changes in systemic immune response in premalignant and malignant oral lesions. Method: The proportions of Neutrophils, Monocytes, Lymphocytes, total T cells, T cell subsets including αβ/γδ T cells, Cytotoxic T cells, Helper T cells, Naive/ Effector/Memory T cells, Regulatory T cells and NK-T subpopulations were analysed in peripheral circulation of healthy donors (N= 49), Leukoplakia (N=20) and OSCC patients (N=100) by flowcytometry. Results: In comparison with healthy donors, decreased Lymphocytes, Naive Helper cells, NK T subpopulations and increased Effector cells were observed in Leukoplakia patients. Similarly, decreased Lymphocytes, NK T subpopulations and increased Neutrophils, Monocytes, Helper and Regulatory T cells were observed in OSCC patients as compared to healthy controls. Moreover, Lymphocytes were decreased and Regulatory T cells were increaed during the progression of Leukoplakia to OSCC. Further, in relation with clinicopathological parameters, Cytotoxic cells were found to be reduced with increasing histological grade. Also, Helper cells were found to be decreased in patients with tobacco and alcohol habit and also with increasing tumor size. Further, in univariate survival analysis, increased incidence of relapse was observed in patients with low γδ and NK T cells. In multivariate survival analysis, low γδ T cells emerged as poor prognosticator for disease free survival and high Regulatory T cells emerged as poor prognosticator for predicting overall survival. Conclusion: Altered systemic immune response was seen during malignant transformation and also found to be associated with patient’s survival. Thus, investigation of circulating Leukocyte and T cell subsets seems to be useful for predicting patient’s survival and to identify immunosuppressed patients who may be benefited with immunotherapy.

IL-17 as an important effector cytokine in a mouse model for S.typhimurium sepsis

Background Naive CD4 helper T cells differentiate after TCR activation into the 3 characterizing cytokine-secreting effector cells: TH-1, TH-2, and TH-17. The TH-17 lineage is characterized by IL-17 production and is induced by IL-23, IL-6 and TGF-s. The role of iron in IL-17-mediated immune functions however, has not been elucidated thus far. Herein, we investigated the involvement of IL-17 in immune response against S. typhimurium.

IL-4 can inhibit IL-17 production in collagen induced arthritis.

IL-4 is a cytokine that induces differentiation of naive helper T cells into Th2 cells. Once activated by IL-4, Th2 cells subsequently produce additional IL-4. To examine the effect of IL-4 on IL-17 production and its effect in Collagen-Induced Arthritis (CIA) mice. In this study, a chicken collagen-II-induced experimental arthritis (CIA) model was used in DBA/1 mice to investigate the relationship between IL-4 and IL-17 as well as other inflammatory factors. On the 38th day after the mice were induced with CIA, the expression of IL-17 and IL-4 as well as IFN-γ and IL-13 in sera of the mice was measured by QRT-PCR and ELISA. The result of QRT-PCR analysis of IL-17 and IL-4 mRNA levels in the spleen showed that IL-17 is increased significantly at the onset of CIA in the spleen (p<0.01). Meanwhile, IL-17 is generally reduced at the peak of CIA but IL-4 is increased significantly at this peak in the spleen when the weight of the animal was taken into consideration (p<0.05). IL-4 can be involved in the production of IL-17 at especially the peak of CIA. These results imply that the inhibition of IL-17 may decrease the expression of IL-1β and IL-6 production which will result in the aggravation of arthritis.