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

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

Science Immunology ◽

10.1126/sciimmunol.abb6852 ◽

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.162.1.117 ◽

1985 ◽

Vol 162 (1) ◽

pp. 117-127 ◽

Cited By ~ 221

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.

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Peripheral B Cells from Patients with MGUS and Multiple Myeloma (MM) Can Be Stimulated by Paraprotein-Target Specific T-Helper Cells to Produce Paraprotein-Identical Monoclonal Antibodies: Rationale for PARs, a Novel Therapeutic Approach with Ultimate Specificity in MGUS/MM

Blood ◽

10.1182/blood.v126.23.1817.1817 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1817-1817

Author(s):

Frank Neumann ◽

Boris Kubuschok ◽

Klaus-Dieter Preuss ◽

Claudia Schormann ◽

Michael Pfreundschuh

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

T Helper Cells ◽

Plasma Cells ◽

T Helper ◽

Helper Cells ◽

Hla Dr ◽

Peripheral B Cells

Abstract Background: Paratarg-7 (P-7) is the antigenic target of paraproteins(Preuss et al. Int J Cancer 2009;125:656-61) from 15% of European and 37% of African-American MGUS/MM patients, stronlgy supporting a role of P-7 in the pathogenesis of MGUS/MM via chronic auto-antigenic stimulation. All patients with P-7 specific paraproteins are carriers of the hyperphosphorylated version of p-7 (pP-7). We recently identified pP-7 specific T-helper cells which were restricted by certain "permissive" HLA-DR haplotypes (Neumann et al., Int J Cancer 2015; 137:1076-1084). These HLA-DR subtypes are overrepresented among patients with P-7 specific paraproteins compared to the corresponding normal population indicating that there are two prerequisites for the development of MGUS/MM with a P-7 specific paraprotein: 1st carriership of pP-7 and 2nd a permissive HLA-DR subtype. We now investigated the functional role of the pP-7 specific T-helper cells and their interaction with peripheral B cells with cognate specificity. Methods: Three patients with MGUS or MM, respectively, with a P-7 specific paraprotein and pP-7 specific T-helper cells were included in this study so far. In addition, the B cells from one healthy pP-7 carrying son of one of the patients were also analyzed. In vitro stimulation of antigen-specific peripheral B cells by pP-7 specific T-helper cells followed a modified protocol previously described by Lanzavecchia et al. (Eur J Immunol. 1983; 13:733-738). To this end, CD19+ B cells and CD3+ T cells were magnetically isolated from the proband's PBMC. T cells were replaced by corresponding T-helper cell clones. Results: In all patients studied, the autologous pP-7 specific T-helper cells stimulated the peripheral B cells to produce P-7 specific antibodies. The P-7 specific B-cell responses were monoclonal and the immunoglobulin type was the same as the paraprotein of the corresponding patient. In contrast, B-cell stimulation with CMV-pp65 specific T-helper cells used as controls always induced an antigen-specific, yet polyclonal response. When the peripheral B cells of a pP-7 carrying patient's son were also stimulated with pP-7 specific T-helper cells, they induced - in contrast to the mother - a polyclonal P-7 specific antibody response in his B cells, even though mother and son shared a "permissive" HLA-DR haplotype (HLA-DRB1*1301). Conclusion: In patients with MGUS/MM monoclonal B cells are found in the peripheral blood that can be induced to produce monoclonal antibodies identical to the serum paraprotein by T-helper cells with specificity for the antigenic target of the paraprotein. This does not only support an indispensable role of these T-helper cells in the pathogenesis of MGUS/MM via chronic antigenic stimulation, it also proves that precursors of the malignant plasma cells can be found in the peripheral blood that might fuel the development of malignant plasma cells. Cytogenetic and molecular genetic analyses are underway to determine if these precursor B-cells share the malignant genotype of their malignant plasma cells. These B cells can now be targeted by PARs (p araprotein a ntigens for r everse targeting) conjugated to toxins, as parts of bispecific constructs (PAR/CD3 or PAR/CD16) and/or PAR/CAR T cells. Use of PARs can be envisaged prophylactically for carriers of modified autoantigens like pP-7 with a permissive HLA-DR haplotype and a monoclonal B-cell response in vitro or in MM patients achieving a VGPR or CR after treatment for the prevention of relapse. Disclosures No relevant conflicts of interest to declare.

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Faculty Opinions recommendation of Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5389963.5737054 ◽

2010 ◽

Author(s):

Takeshi Tsubata

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

T Helper Cells ◽

T Helper ◽

Helper Cells ◽

Self Tolerance ◽

Follicular T Helper Cells

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Faculty Opinions recommendation of Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5389963.5630057 ◽

2010 ◽

Author(s):

Kazuhiko Yamamoto ◽

Akiko Okamoto

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

T Helper Cells ◽

T Helper ◽

Helper Cells ◽

Self Tolerance ◽

Follicular T Helper Cells

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

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2021-0375 ◽

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.

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Role of accessory cells in cytokine production by T cells in chronic B- cell lymphocytic leukemia

Blood ◽

10.1182/blood.v86.3.1115.1115 ◽

1995 ◽

Vol 86 (3) ◽

pp. 1115-1123 ◽

Cited By ~ 31

Author(s):

T Decker ◽

T Flohr ◽

P Trautmann ◽

MJ Aman ◽

W Holter ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

T Helper Cells ◽

Cytokine Production ◽

Lymphocytic Leukemia ◽

T Helper ◽

Ifn Gamma ◽

Helper Cells ◽

Accessory Cells ◽

Normal Individuals

Abstract We investigated the production of cytokines by highly purified T helper cells from B-cell chronic lymphocytic leukemia (B-CLL) patients stimulated by different activation pathways, and we studied the influence of various accessory cell populations on the pattern of the secretion of cytokines, including interleukin (IL)-2, IL-4, interferon- gamma (IFN-gamma), and IL-10. Neither a qualitative nor a quantitative difference in cytokine production and proliferative capacity was observed in CLL-derived purified T cells compared with normal individuals, when T cells were stimulated by different pathways, including CD3, CD2, and costimulation with CD28. Addition of autologous accessory cells (aAC), however, dramatically influenced the cytokine pattern of normal versus B-CLL-derived T cells. CLL cells as aAC caused a marked increase of IL-2, whereas IFN-gamma was only slightly induced and IL-4 was not influenced. In contrast, in normal individuals addition of aAC, which predominantly consisted of monocytes, resulted in a significant increase of IFN-gamma and a reduction of IL-4 secretion. IL-2 production was inhibited by higher concentrations of aAC. The increased stimulation of IL-2 production by CLL cells was not specific to the leukemic cell population, as purified B cells from normal individuals had the same effect. On the other hand, purified monocytes from CLL patients and controls both induced IFN-gamma production and inhibited IL-4 secretion. After antigen-specific stimulation with tetanus toxoid, cytokine secretion was influenced by the type of aAC in a similar pattern. We conclude that T helper cells derived from patients with B-CLL are intrinsically normal and that the predominance of B cells as accessory cells in CLL significantly alters the immune function of T helper cells in vitro.

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An idiotype-specific helper population that bears immunoglobulin, Ia, and Lyt-1 determinants.

Journal of Experimental Medicine ◽

10.1084/jem.159.4.1189 ◽

1984 ◽

Vol 159 (4) ◽

pp. 1189-1200 ◽

Cited By ~ 32

Author(s):

D H Sherr ◽

M E Dorf

Keyword(s):

T Cells ◽

B Cells ◽

Cell Population ◽

T Helper Cells ◽

T Helper ◽

Phenotypic Characteristics ◽

Surface Phenotype ◽

Specific Recognition ◽

Helper Cells ◽

Helper Activity

A helper cell population with phenotypic characteristics of both B and T cells is described. This helper population, called BH, is present in normal unprimed C57BL/6 mice and preferentially helps the expression of NPb idiotype-bearing plaque-forming B cells in the absence of T helper cells. Its surface phenotype is Lyt-1.2+, Ig+, Lyb-3+, Thy-1.2-, Lyt-2.2-. The helper activity of the BH population is IgH restricted and BH cells selectively bind NPb idiotypic determinants. Collectively the data demonstrate that this unique subpopulation can regulate the response of antibody-secreting B cells through specific recognition of idiotypic determinants.

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