Renewal of the T-cell compartment in multiple sclerosis patients treated with glatiramer acetate

2009 ◽  
Vol 16 (2) ◽  
pp. 218-227 ◽  
Author(s):  
M. Chiarini ◽  
A. Sottini ◽  
C. Ghidini ◽  
C. Zanotti ◽  
F. Serana ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Glatiramer Acetate ◽  
T Helper Cells ◽  
T Cell Repertoire ◽  
T Helper ◽  
Cell Repertoire ◽  
Helper Cells ◽  
Cell Diversity ◽  
Multiple Sclerosis Patients

The immunomodulating activity of glatiramer acetate on T-cells of multiple sclerosis patients has only been partially clarified. The objective of this work was to investigate whether glatiramer acetate modifies thymic release of newly produced T-cells and the peripheral composition of the T-cell repertoire. T-cell receptor excision circles, thymic naive (CD4+CD45RA+CCR7 +CD31+) T helper cells, and central (CD4+CD45RA -CCR7+) and effector (CD4+CD45RA-CCR7 -) memory T-cells were evaluated in 89 untreated patients, 84 patients treated for at least 1 year, and 31 patients beginning treatment at the time of inclusion in the study and then followed-up for 12 months; controls were 81 healthy donors. The T-cell repertoire was analysed in selected samples. The percentage of thymicnaive T helper cells was diminished in untreated patients, but rose to control values in treated subjects; a decrease in central memory T-cells was also observed in treated patients. Follow-up patients could be divided into two subgroups, one showing unmodified thymicnaive T helper cells and T-cell diversity, the other in which the increased release of new T-cells was accompanied by modifications of the T-cell repertoire. Glatiramer acetate modifies the peripheral T-cell pool by activating a thymopoietic pathway of T-cell release that leads to a different setting of T-cell diversity and, likely, to a dilution of autoreactive T-cells.

scholarly journals Follicular T helper cells shape the HCV-specific CD4+ T cell repertoire after virus elimination

2020 ◽  
Vol 130 (2) ◽  
pp. 998-1009 ◽  
Author(s):  
Maike Smits ◽  
Katharina Zoldan ◽  
Naveed Ishaque ◽  
Zuguang Gu ◽  
Katharina Jechow ◽  
...  
Keyword(s):  
T Cell ◽  
T Helper Cells ◽  
Cd4 T Cell ◽  
T Cell Repertoire ◽  
T Helper ◽  
Cell Repertoire ◽  
Virus Elimination ◽  
Helper Cells ◽  
Follicular T Helper Cells

scholarly journals Neonatal lymphocyte subpopulations analysis and maternal preterm premature rupture of membranes: a pilot study

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Margherita Amadi ◽  
Silvia Visentin ◽  
Francesca Tosato ◽  
Paola Fogar ◽  
Giulia Giacomini ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
T Helper Cells ◽  
Lymphocyte Subpopulations ◽  
T Helper ◽  
Premature Rupture Of Membranes ◽  
Premature Rupture ◽  
Preterm Premature Rupture ◽  
Helper Cells

Abstract Objectives Preterm premature rupture of membranes (pPROM) causes preterm delivery, and increases maternal T-cell response against the fetus. Fetal inflammatory response prompts maturation of the newborn’s immunocompetent cells, and could be associated with unfavorable neonatal outcome. The aims were to examine the effects of pPROM (Mercer BM. Preterm premature rupture of the membranes: current approaches to evaluation and management. Obstet Gynecol Clin N Am 2005;32:411) on the newborn’s and mother’s immune system and (Test G, Levy A, Wiznitzer A, Mazor M, Holcberg G, Zlotnik A, et al. Factors affecting the latency period in patients with preterm premature rupture of membranes (pPROM). Arch Gynecol Obstet 2011;283:707–10) to assess the predictive value of immune system changes in neonatal morbidity. Methods Mother-newborn pairs (18 mothers and 23 newborns) who experienced pPROM and controls (11 mothers and 14 newborns), were enrolled. Maternal and neonatal whole blood samples underwent flow cytometry to measure lymphocyte subpopulations. Results pPROM-newborns had fewer naïve CD4 T-cells, and more memory CD4 T-cells than control newborns. The effect was the same for increasing pPROM latency times before delivery. Gestational age and birth weight influenced maturation of the newborns’ lymphocyte subpopulations and white blood cells, notably cytotoxic T-cells, regulatory T-cells, T-helper cells (absolute count), and CD4/CD8 ratio. Among morbidities, fewer naïve CD8 T-cells were found in bronchopulmonary dysplasia (BPD) (p=0.0009), and more T-helper cells in early onset sepsis (p=0.04). Conclusions pPROM prompts maturation of the newborn’s T-cell immune system secondary to antigenic stimulation, which correlates with pPROM latency. Maternal immunity to inflammatory conditions is associated with a decrease in non-major histocompatibility complex (MHC)-restricted cytotoxic cells.

scholarly journals The B cell repertoire revealed by major histocompatibility complex-specific helper T cells. I. Frequencies of a genetically defined V region marker among mitogen- and T helper cell-reactive B lymphocytes in normal and immunized mice.

1984 ◽  
Vol 159 (4) ◽  
pp. 1253-1269 ◽  
Author(s):  
D Primi ◽  
P A Cazenave
Keyword(s):  
T Cell ◽  
B Cell ◽  
T Helper Cells ◽  
Early Stage ◽  
Cell Subset ◽  
Gene Repertoire ◽  
T Helper ◽  
Cell Repertoire ◽  
Helper Cells ◽  
V Region

The aim of the present work was to analyze the frequencies of a genetically defined variable (V) region marker in the B cell subset sensitive to T cell help. To this end we used an alloreactive T cell line that has the property of inducing B cells of the appropriate haplotype to exponential growth and polyclonal antibody synthesis. The frequency obtained with this helper line was also directly compared to that obtained with lipopolysaccharide (LPS). We found that in normal BALB/c mice the frequency of M460-positive clonotypes was respectively, 1/100 and 1/1,000 among the T helper- and LPS-sensitive B cell subsets. In mice immunized with antiidiotype coupled to a thymus-dependent antigen, the differences in the numbers of idiotype-positive precursors were even more accentuated, i.e. 1/20 in the B cell subset triggered by T helper cells and 1/800 in those cells responsive to LPS. The frequencies of the M460 determinant in mice immunized with anti-idiotypes coupled to thymus-independent antigens were not significantly different, in either B cell subset, from those obtained with spleen cells of normal nonimmunized animals. Taken as a whole, our results imply that the V gene repertoire revealed by LPS includes precursor distribution, as this distribution occurs during the early stage of B cell development (potential repertoire), while the repertoire revealed by T helper cells includes the V region distribution of those clones that are selected in the periphery of the functional immune system.

scholarly journals Tissue-resident CD4+ T helper cells assist the development of protective respiratory B and CD8+ T cell memory responses

2021 ◽  
Vol 6 (55) ◽  
pp. eabb6852
Author(s):  
Young Min Son ◽  
In Su Cheon ◽  
Yue Wu ◽  
Chaofan Li ◽  
Zheng Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Helper Cells ◽  
Critical Role ◽  
Cell Formation ◽  
Influenza Virus Infection ◽  
T Helper ◽  
Helper Cells ◽  
Cell Immunity

Much remains unknown about the roles of CD4+ T helper cells in shaping localized memory B cell and CD8+ T cell immunity in the mucosal tissues. Here, we report that lung T helper cells provide local assistance for the optimal development of tissue-resident memory B and CD8+ T cells after the resolution of primary influenza virus infection. We have identified a population of T cells in the lung that exhibit characteristics of both follicular T helper and TRM cells, and we have termed these cells as resident helper T (TRH) cells. Optimal TRH cell formation was dependent on transcription factors involved in T follicular helper and resident memory T cell development including BCL6 and Bhlhe40. We show that TRH cells deliver local help to CD8+ T cells through IL-21–dependent mechanisms. Our data have uncovered the presence of a tissue-resident helper T cell population in the lung that plays a critical role in promoting the development of protective B cell and CD8+ T cell responses.

scholarly journals Tissue-resident CD4+ T helper cells assist protective respiratory mucosal B and CD8+ T cell memory responses

2020 ◽  
Author(s):  
Young Min Son ◽  
In Su Cheon ◽  
Yue Wu ◽  
Chaofan Li ◽  
Zheng Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Helper Cells ◽  
Cell Formation ◽  
Influenza Virus Infection ◽  
T Helper ◽  
Helper Cells ◽  
Mucosal Tissues ◽  
Cell Immunity ◽  
Cd8 T Cell Memory

AbstractThe roles of CD4+ T helper cells (TH) in shaping localized memory B and CD8+ T cell immunity in the mucosal tissues are largely unexplored. Here, we report that lung TH cells provide local assistance for the optimal development of tissue-resident memory B (BRM) and CD8+ T (TRM) cells following the resolution of primary influenza virus infection. We identify a population of tissue-resident CD4+ TH (aka TRH) cells that co-exhibit follicular T helper (TFH) and TRM cell features and mediate local help of CD4+ T cells to B and CD8+ T cells. Optimal TRH cell formation requires lung B cells and transcription factors involved in TFH or TRM development. Further, we show that TRH cells deliver local help to B and CD8 T cells through CD40L and IL-21-dependent mechanisms. Our data have uncovered a new tissue-resident TH cell population that is specialized in assisting the development of mucosal protective B and CD8+ T cell responses in situ.

scholarly journals Ripk3 Signaling Restricts the Development of Peripheral T Cell Lymphoma in Tet2 Deficient Mice

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3318-3318
Author(s):  
Kanak Joshi ◽  
Ryan Mack ◽  
Lei Zhang ◽  
Shanhui Liu ◽  
Mark Sellin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
T Helper Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Wild Type ◽  
T Helper ◽  
Peripheral T Cell Lymphoma ◽  
Helper Cells

Abstract Inactive mutations of the Ten-eleven translocation (TET2) gene are commonly found in humans with multiple hematological malignancies including myeloproliferative neoplasm (MPN), acute myeloid leukemia, diffuse large B cell lymphoma, and peripheral T cell lymphomas (PTCL), and are frequently associated with poor prognosis and worse overall survival. TET2 mutations often occur in hematopoietic stem and progenitor cells (HSPCs) and are known to collaborate with additional mutations for full-blown malignant transformation. However, the molecular mechanism by which the disease identity is determined remains to be elucidated. Increased inflammatory cytokines are commonly detected in patients with TET2 mutations, which is associated with an increased risk of atherosclerotic cardiovascular diseases. Most Tet2 knockout (Tet2 -/-) mice develop MPN-like disease within 18 months, with only a few cases developing chronic lymphocyte leukemia-like disease at two years of age. The intestinal bacteria-induced inflammatory signaling plays a critical role in the pathogenesis of MPN-like disease in Tet2 -/- mice. Receptor-interacting protein kinase 3 (Ripk3) is a key mediator of inflammation cytokine-induced necroptosis and metabolic signaling. Compared to bone marrow (BM) cells isolated from wild-type mice, higher levels of Ripk3 activity can be detected in Tet2 -/- BM cells. To study the role of Ripk3 in Tet2 mutations associated with hematopoietic diseases, we crossed Tet2 conditional knockout (Tet2fx/fx Mx1-Cre +) mice with Ripk3 -/- mice to generate Tet2 and Ripk3 compound knockout (Tet2 -/-Ripk3 -/-) mice. Tet2 -/-Ripk3 -/- mice developed aggressive tumors by 12-15 months of age as characterized by profound hepatosplenomegaly and lymphadenopathy, with substantial lymphocytosis, neutrophilia, anemia, and thrombocytopenia. Histopathological analysis revealed an aggressive infiltration of tumor cells in the liver and spleen, and effacement of splenic follicular structures in diseased Tet2 -/-Ripk3 -/- mice. To characterize the type of malignancies, single-cell suspensions of the BM, peripheral blood (PB), and spleen from Tet2 -/-Ripk3 -/- were analyzed by flow cytometry and compared with wild-type and Tet2 -/- mice. As expected Tet2 -/- mice exhibited increased frequencies of myeloid cells in the PB, BM, and spleen. However, there was a marked expansion of CD4 + T cells in the PB, BM, and spleen of Tet2 -/-Ripk3 -/- mice. Detailed analyses of the T subsets demonstrated a marked expansion of both CD4 +PD1 +CXCR5 + follicular T helper cells (T fh) and CD4 +PD1 + peripheral T helper cells (T ph), indicating the development of a peripheral T cell lymphoma (PTCL) in the Tet2 -/-Ripk3 -/- mice. Additionally, disease characteristics including the reduced surface expression of CD3 in the tumor cells, increased levels of classical T h cytokines in the serum, as well as the presence of heterogeneous populations of cells within the tumor tissues recapitulate the pathological features of angioimmunoblastic T cell lymphoma (AITL), a subtype of PTCL. Elevated frequencies of splenic T fh and T ph cells were detected as early as 7 months of age in Tet2 -/-Ripk3 -/- mice. Such cells expressed inducible T cell costimulatory receptor (ICOS), an essential signaling mediator of the T fh development and proliferation. However, all other hematopoietic parameters including BM HSPCs and mature CD4 + T cells were comparable to wild type and single-gene Tet2 -/- mice. These results indicate that Ripk3 signaling inhibits PTCL development in Tet2 -/- mice by limiting the expansion of T fh and T ph cells. We are currently determining whether Ripk3 plays such a role by inducing necroptosis and/or restricting the differentiation of CD4 + naive T cells into peripheral T fh and T ph populations. We are also investigating whether Ripk3 signaling is inactivated in the tumor cells of human PTCL patients and whether we can treat such aggressive fatal diseases by reactivating Ripk3 signaling. Disclosures No relevant conflicts of interest to declare.

scholarly journals Authentic T helper CD4 (W3/25) antigen on rat peritoneal macrophages.

1985 ◽  
Vol 162 (1) ◽  
pp. 117-127 ◽  
Author(s):  
W A Jefferies ◽  
J R Green ◽  
A F Williams
Keyword(s):  
Molecular Weight ◽  
Monoclonal Antibody ◽  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
B Cells ◽  
T Helper Cells ◽  
Peritoneal Macrophages ◽  
T Helper ◽  
Helper Cells

The rat W3/25 antigen that appears to be equivalent to human CD4 (T4) antigen is expressed on thymocytes and T helper cells and plays a role in the response of T helper cells to antigen. The W3/25 and anti-T4 antibodies also label macrophages. In this paper we examine whether the macrophage antigen is the same as that on T cells. New monoclonal antibodies against the rat CD4 antigen, MRC OX-35 through OX-38, are described, all of which label peritoneal macrophages from normal and athymic rats. The molecular weight of W3/25 antigen on macrophages is indistinguishable from that on T cells. We conclude that macrophages express authentic CD4 (W3/25) antigen. Another new monoclonal antibody, MRC OX-34, labels an antigen of 50-54,000 mol wt that is expressed on rat T but not B cells or peritoneal macrophages. It was used to control for the presence of any T cell products in immunoprecipitation from rat macrophage extracts.

Clonal Diversity of the T Cell Repertoire Predicts Disease Progression in Chronic Lymphocytic Leukaemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 803-803
Author(s):  
Claudia Holler ◽  
Nadja Zaborsky ◽  
Josefina Pinon Hofbauer ◽  
Thomas Kocher ◽  
Doris Trapin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Lymphocytic Leukaemia ◽  
Cd4 T Cell ◽  
T Cell Repertoire ◽  
Cd4 Cells ◽  
Cell Repertoire ◽  
Cell Diversity ◽  
Selection Of

Abstract Abstract 803 Introduction: The development of B cell chronic lymphocytic leukaemia (CLL) involves antigenic selection of the B cell clone, as evidenced by a skewed BCR repertoire found in CLL cells, as well as continuing BCR signaling detected in subgroups of CLL. T cell involvement in the maintenance of the malignant clone is also suggested by a number of evidential lines, such as the severe skewing of T cell subsets in CLL and the presence of relevant numbers of CD4 cells in the so-called “proliferation centers” in lymph nodes. However, neither clonal nor immunologic identities of these T cells have been sufficiently determined. Recently, we have shown in Tcl1 transgenic mice that CLL clones were able to directly drive changes in the T cell repertoire, resulting in relatively fast skewing in subset distribution (similar to that observed in human CLL) as well as a clonal selection of T cells, both in spontaneously developing CLL in the model, as well as in immunocompetent congenic recipient mice in experiments transplanting established murine CLL. Methods: To establish evidence for similar interactions in human CLL, we collected a descriptive database determining patterns of T cell diversity in CLL patient blood. We analyzed T cells from 53 previously-untreated CLL patients established TCR V beta clonality and frequency based on CDR3 length polymorphism in sorted CD4 cells and, in a confirmatory subset, based on TCR V gene-specific flow cytometry. CLL samples were also investigated regarding the BCR VH gene usage, mutation status and clinical and prognostic parameters. Results: BCR analysis confirmed antigenic selection in our patient set with 6 IgVH genes accounting for > 50% of the cases. Stereotyped CDR3 regions were common and one third of the patients showed unmutatetd IgVH gene sequence. Analysing 20 TCR genes by PCR spectratyping, the TCR CDR3 size distribution pattern revealed a relevant frequency of oligoclonal/monoclonal CD4 T cells in CLL samples. While a number of patients showed completely polyclonal patterns in all their TCR CDR3 regions, others showed either single or multiple clonal TCR families. In corresponding flow cytometric analyses clonal T cells could make up to 48% of total CD4 cells in a given patient. In patients with longitudinal samples we found relevant stability of these TCR patterns over time. By comparing the data from the TCR clonality database with our BCR dataset we established that these clonal patterns significantly, but not exclusively, clustered in unmutated patient samples. Overall we found no strong association with any specific IgVH gene, but intriguingly, in some patients a specific clonal TCR corresponded to a stereotyped BCR receptor. In fact in two patient pairs with identical IgVH rearrangements we found corresponding TCR clones that showed sequence identity between the CD4 T cell clones derived from the other patient. In addition in both pairs we found a shared HLA DR and DQ haplotype. These data strongly suggests that there may be an important link between the antigenic selection on the B-CLL clone and the selection of certain TCR clones, thus for the first time postulating an antigentic identity of the CLL-associated T cells. This proposed identity, however, currently remains unclear. Finally, we tested for an influence of T cell clonality on clinical behaviour of CLL disease in the patients. We could intentify the presence of more than one clonal TCR family as a significant predictor of a short treatment-free interval (p=0.03). This was true for both, patients with mutated and unmutated IgVH receptors, although it remained a trend in the latter. Conclusion: Our results imply that a restricted CD4 T cell diversity may be important for CLL progression and that an as of yet still undefined antigenic drive for T cells may be important for this. This may help to define specific monoclonal CD4 T cells as a promising novel target for future therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.

Vaccine-Induced, Pseudorabies Virus-Specific, Extrathymic CD4+CD8+ Memory T-Helper Cells in Swine

1998 ◽  
Vol 72 (6) ◽  
pp. 4866-4873 ◽  
Author(s):  
Bertram T. Ober ◽  
Artur Summerfield ◽  
Christina Mattlinger ◽  
Karl-Heinz Wiesmüller ◽  
Günther Jung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Mhc Class Ii ◽  
T Helper Cells ◽  
Pseudorabies Virus ◽  
Class Ii ◽  
T Cell Epitopes ◽  
T Helper ◽  
Helper Cells

ABSTRACT Pseudorabies virus (PRV; suid herpesvirus 1) infection causes heavy economic losses in the pig industry. Therefore, vaccination with live attenuated viruses is practiced in many countries. This vaccination was demonstrated to induce extrathymic virus-specific memory CD4+CD8+ T lymphocytes. Due to their major histocompatibility complex (MHC) class II-restricted proliferation, it is generally believed that these T lymphocytes function as memory T-helper cells. To directly prove this hypothesis, 15-amino-acid, overlapping peptides of the viral glycoprotein gC were used for screening in proliferation assays with peripheral blood mononuclear cells of vaccinated d/d haplotype inbred pigs. In these experiments, two naturally processed T-cell epitopes (T1 and T2) which are MHC class II restricted were identified. It was shown that extrathymic CD4+CD8+ T cells are the T-lymphocyte subpopulation that responds to epitope T2. In addition, we were able to show that cytokine secretion can be induced in these T cells through recall with inactivated PRV and demonstrated that activated PRV-primed CD4+CD8+ T cells are able to induce PRV-specific immunoglobulin synthesis by PRV-primed, resting B cells. Taken together, these results demonstrate that the glycoprotein gC takes part in the priming of humoral anti-PRV memory responses. The experiments identified the first T-cell epitopes so far known to induce the generation of virus-specific CD4+CD8+ memory T lymphocytes and showed that CD4+CD8+ T cells are memory T-helper cells. Therefore, this study describes the generation of virus-specific CD4+CD8+ T cells, which is observed during vaccination, as a part of the potent humoral anti-PRV memory response induced by the vaccine.

Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 1924-1931 ◽  
Author(s):  
Svenja Hardtke ◽  
Lars Ohl ◽  
Reinhold Förster
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Helper Cells ◽  
Cell Area ◽  
T Helper ◽  
Helper Cells ◽  
Follicular T Helper Cells ◽  
Cell Follicle

Abstract The production of high-affinity antibodies to T-dependent antigens requires the interaction of B cells and T helper cells expressing receptors specific for the same antigen. Although several mechanisms have been elucidated that regulate B-cell trafficking within lymphoid organs, less is known about molecular cues that guide the small subpopulation of CD4+ follicular T helper cells to B-cell follicles. Using adoptive transfer of transgenic T cells in mice, we demonstrate that antigen-induced activation leads to a finely tuned positioning of T cells either to the T-cell area or the B-cell follicle. We show that expression of CXCR5 is indispensable for T cells to enter B-cell follicles, whereas expression of CCR7 provides a counteracting signal to retain activated T cells in the T-cell area. Although only few T cells transiently migrate from the T-cell area to the B-cell follicle of peripheral lymph nodes following antigenic challenge, this step is essential to provide the help B cells require to produce antibodies efficiently. Thus, we demonstrate that the balanced expression of CCR7 and CXCR5 determines the positioning and proper function of follicular T helper cells.

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