Co-stimulation with 4-1BB ligand allows extended T-cell proliferation, synergizes with CD80/CD86 and can reactivate anergic T cells

It has been proposed that some bystander T cell activation may in fact be due to T cell antigen receptor (TCR) cross-reactivity that is too low to be detected by the effector cytotoxic T lymphocyte (CTL). However, this hypothesis is not supported by direct evidence since no TCR ligand is known to induce T cell proliferation and differentiation without being recognized by the effector CTL. Here we report that transgenic T cells expressing a T cell receptor to influenza virus A/NT/68 nucleoprotein (NP) 366-374:Db complexes clonally expand and become effector CTLs in response to homologous peptides from either A/PR8/34 (H1N1), A/AA/60 (H2N2), or A/NT/68 (H3N2). However, the effector T cells induced by each of the three peptides kill target cells pulsed with NP peptides from the H3N2 and H2N2 viruses, but not from the H1N1 virus. Thus, NP366–374 from influenza virus H1N1 is the first TCR ligand that can induce T cell proliferation and differentiation without being recognized by CTLs. Since induction of T cell proliferation was mediated by antigen-presenting cells that express costimulatory molecules such as B7, we investigated if cytolysis of H1N1 NP peptide–pulsed targets can be restored by expressing B7-1 on the target cells. Our results revealed that this is the case. These data demonstrated that costimulatory molecule B7 modulates antigen specificity of CTLs, and provides a missing link that explains some of the bystander T cell activation.

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Decreased concanavalin A-stimulated T cell proliferation in patients with Sjögren’s syndrome — dysfunction of peripheral blood dendritic cells and T cells

Japanese Journal of Rheumatology ◽

10.3109/bf03041345 ◽

1998 ◽

Vol 8 (2) ◽

pp. 205-211

Author(s):

Yuji Akiyama ◽

Satoru Odagiri ◽

Fumihiko Imai ◽

Toshiko Ishibashi ◽

Teruhiko Suzuki

Keyword(s):

Cell Proliferation ◽

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Concanavalin A ◽

Peripheral Blood ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

T Cell Proliferation ◽

Sjögren‘S Syndrome

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Relative impact of CD4+CD25+ regulatory T cells and tacrolimus on inhibition of T-cell proliferation in patients with atopic dermatitis

British Journal of Dermatology ◽

10.1111/j.1365-2133.2005.06675.x ◽

2005 ◽

Vol 153 (4) ◽

pp. 750-757 ◽

Cited By ~ 25

Author(s):

M. Vukmanovic-Stejic ◽

A. McQuaid ◽

K.E. Birch ◽

J.R. Reed ◽

C. Macgregor ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

Atopic Dermatitis ◽

T Cell ◽

Regulatory T Cells ◽

T Cell Proliferation ◽

Relative Impact

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T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression

Molecular and Cellular Biology ◽

10.1128/mcb.7.12.4472-4481.1987 ◽

1987 ◽

Vol 7 (12) ◽

pp. 4472-4481

Author(s):

C H June ◽

J A Ledbetter ◽

M M Gillespie ◽

T Lindsten ◽

C B Thompson

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Interleukin 2 ◽

Cell Receptor ◽

T Cell Proliferation ◽

Cd28 Molecule ◽

T Cell Stimulation ◽

Protein Kinase C Activation

CD28 is a homodimeric glycoprotein expressed on the surface of a major subset of human T cells that has recently been identified as a member of the immunoglobulin supergene family. The binding of monoclonal antibodies to the CD28 antigen on purified T cells does not result in proliferation; however, previous studies have shown that the combination of CD28 stimulation and protein kinase C activation by phorbol myristate acetate (PMA) results in T-cell proliferation that is independent of both accessory cells and activation of the T-cell receptor-CD3 complex. In the present study, effects of stimulation by anti-CD28 on cell cycle progression and on the interleukin 2 (IL-2) and IL-2 receptor system have been investigated on primary cultures of purified peripheral-blood CD28+ T cells. There was no measurable effect on cell size or on DNA synthesis after stimulation of resting (G0) cells by CD28 alone. After 3 h of activation of T cells by PMA alone, a slight (8%) increase in cell volume occurred that did not progress to DNA synthesis. In contrast, T-cell stimulation by CD28 in combination with PMA resulted in a progressive increase in cell volume in approximately 100% of cells at 12 to 14 h after stimulation. Northern blot (RNA blot) analysis revealed that CD28 stimulation alone failed to cause expression of the alpha chain of the IL-2 receptor or of IL-2 mRNA, and in accord with previous studies, stimulation by PMA alone resulted in the accumulation of IL-2 receptor transcripts but no detectable IL-2 mRNA. In contrast, T-cell stimulation by the combination of CD28 and PMA resulted in the appearance of IL-2 transcripts and enhanced expression of IL-2 receptor mRNA. Functional studies revealed that the proliferation induced by CD28 and PMA stimulation was entirely resistant to cyclosporine, in contrast to T-cell activation induced by the CD3-T-cell receptor complex. Cyclosporine was found not to affect the accumulation of IL-2 mRNA after CD28 plus PMA stimulation, although there was no detectable IL-2 mRNA after stimulation by CD3 in the presence of the drug. Furthermore, stimulation by CD28 in combination with immobilized CD3 antibodies caused a striking enhancement of IL-2 mRNA expression that was, in part, resistant to the effects of cyclosporine. These studies indicate that the CD28 molecule synergizes with protein kinase C activation to induce IL-2 gene expression and demonstrate that stimulation by the CD28 pathway can cause vigorous T-cell proliferation even in the presence of cyclosporine and that cyclosporine does not prevent transcription of 16-2 mRNA, as has been suggested previously. Moreover, these findings suggest that a potential role for the CD28 molecule in vivo may be to augment IL-2 production after stimulation of the CD3-T-cell receptor molecular complex and thereby to amplify an antigen-specific immune response. Finally, these results provide further evidence that the CD28 molecule triggers T-cell proliferation in a manner that differs biochemically from CD3-T-cell receptor-induced proliferation.

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Siplizumab, an Anti-CD2 Monoclonal Antibody, Induces a Unique Set of Immune Modulatory Effects Compared to Alemtuzumab and Rabbit Anti-Thymocyte Globulin In Vitro

Frontiers in Immunology ◽

10.3389/fimmu.2020.592553 ◽

2020 ◽

Vol 11 ◽

Author(s):

Christian Binder ◽

Felix Sellberg ◽

Filip Cvetkovski ◽

Erik Berglund ◽

David Berglund

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Mixed Lymphocyte Reaction ◽

T Cell Proliferation ◽

Allogeneic Mixed Lymphocyte Reaction ◽

Dependent Cell

Antibodies are commonly used in organ transplant induction therapy and to treat autoimmune disorders. The effects of some biologics on the human immune system remain incompletely characterized and a deeper understanding of their mechanisms of action may provide useful insights for their clinical application. The goal of this study was to contrast the mechanistic properties of siplizumab with Alemtuzumab and rabbit Anti-Thymocyte Globulin (rATG). Mechanistic assay systems investigating antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell phagocytosis and complement-dependent cytotoxicity were used to characterize siplizumab. Further, functional effects of siplizumab, Alemtuzumab, and rATG were investigated in allogeneic mixed lymphocyte reaction. Changes in T cell activation, T cell proliferation and frequency of naïve T cells, memory T cells and regulatory T cells induced by siplizumab, Alemtuzumab and rATG in allogeneic mixed lymphocyte reaction were assessed via flow cytometry. Siplizumab depleted T cells, decreased T cell activation, inhibited T cell proliferation and enriched naïve and bona fide regulatory T cells. Neither Alemtuzumab nor rATG induced the same combination of functional effects. The results presented in this study should be used for further in vitro and in vivo investigations that guide the clinical use of immune modulatory biologics.

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Activation Outcomes Induced in Naïve CD8 T-Cells by Macrophages Primed via “Phagocytic” and Nonphagocytic Pathways

Molecular Biology of the Cell ◽

10.1091/mbc.e07-07-0650 ◽

2008 ◽

Vol 19 (2) ◽

pp. 701-710 ◽

Cited By ~ 10

Author(s):

Isabel María Olazabal ◽

Noa Beatriz Martín-Cofreces ◽

María Mittelbrunn ◽

Gloria Martínez del Hoyo ◽

Balbino Alarcón ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

T Cell Proliferation ◽

Microtubule Organizing Center ◽

Antigen Uptake ◽

Soluble Peptide

The array of phagocytic receptors expressed by macrophages make them very efficient at pathogen clearance, and the phagocytic process links innate with adaptive immunity. Primary macrophages modulate antigen cross-presentation and T-cell activation. We assessed ex vivo the putative role of different phagocytic receptors in immune synapse formation with CD8 naïve T-cells from OT-I transgenic mice and compared this with the administration of antigen as a soluble peptide. Macrophages that have phagocytosed antigen induce T-cell microtubule-organizing center and F-actin cytoskeleton relocalization to the contact site, as well as the recruitment of proximal T-cell receptor signals such as activated Vav1 and PKCθ. At the same doses of loaded antigen (1 μM), “phagocytic” macrophages were more efficient than peptide-antigen–loaded macrophages at forming productive immune synapses with T-cells, as indicated by active T-cell TCR/CD3 conformation, LAT phosphorylation, IL-2 production, and T-cell proliferation. Similar T-cell proliferation efficiency was obtained when low doses of soluble peptide (3–30 nM) were loaded on macrophages. These results suggest that the pathway used for antigen uptake may modulate the antigen density presented on MHC-I, resulting in different signals induced in naïve CD8 T-cells, leading either to CD8 T-cell activation or anergy.

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Mapping of the autophagosomal degradome identifies IL-7Rα as key cargo in proliferating CD4+ T-cells

10.1101/2021.12.08.471825 ◽

2021 ◽

Author(s):

Dingxi Zhou ◽

Mariana Borsa ◽

Daniel J. Puleston ◽

Susanne Zellner ◽

Jesusa Capera ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Surface Expression ◽

T Cell Proliferation ◽

Gamma Chain ◽

Direct Identification ◽

The Common ◽

First Time

CD4+ T cells orchestrate both humoral and cytotoxic immune responses. While it is known that CD4+ T cell proliferation relies on autophagy, direct identification of the autophagosomal cargo involved is still missing. Here, we created a transgenic mouse model, which, for the first time, enables us to directly map the proteinaceous content of autophagosomes in any primary cell by LC3 proximity labelling. IL-7Rα, a cytokine receptor mostly found in naive and memory T cells, was reproducibly detected in autophagosomes of activated CD4+ T cells. Consistently, CD4+ T cells lacking autophagy showed increased IL-7Rα surface expression, while no defect in internalisation was observed. Mechanistically, excessive surface IL-7Rα sequestrates the common gamma chain, impairing the IL-2R assembly and downstream signalling crucial for T cell proliferation. This study provides proof-of-principle that key autophagy substrates can be reliably identified with this model to help mechanistically unravel autophagy's contribution to healthy physiology and disease.

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Expansion of Functional Myeloid-Derived Suppressor Cells in Controlled Human Malaria Infection

Frontiers in Immunology ◽

10.3389/fimmu.2021.625712 ◽

2021 ◽

Vol 12 ◽

Author(s):

Carlos Lamsfus Calle ◽

Rolf Fendel ◽

Anurag Singh ◽

Thomas L. Richie ◽

Stephen L. Hoffman ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Immune Responses ◽

Malaria Infection ◽

Malaria Vaccine ◽

Suppressor Cells ◽

T Cell Proliferation ◽

Myeloid Derived Suppressor Cells ◽

Controlled Human Malaria Infection

Malaria can cause life-threatening complications which are often associated with inflammatory reactions. More subtle, but also contributing to the burden of disease are chronic, often subclinical infections, which result in conditions like anemia and immunologic hyporesponsiveness. Although very frequent, such infections are difficult to study in endemic regions because of interaction with concurrent infections and immune responses. In particular, knowledge about mechanisms of malaria-induced immunosuppression is scarce. We measured circulating immune cells by cytometry in healthy, malaria-naïve, adult volunteers undergoing controlled human malaria infection (CHMI) with a focus on potentially immunosuppressive cells. Infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) were inoculated during two independent studies to assess malaria vaccine efficacy. Volunteers were followed daily until parasites were detected in the circulation by RT-qPCR. This allowed us to analyze immune responses during pre-patency and at very low parasite densities in malaria-naïve healthy adults. We observed a consistent increase in circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in volunteers who developed P. falciparum blood stage parasitemia. The increase was independent of preceding vaccination with a pre-erythrocytic malaria vaccine. PMN-MDSC were functional, they suppressed CD4+ and CD8+ T cell proliferation as shown by ex-vivo co-cultivation with stimulated T cells. PMN-MDSC reduced T cell proliferation upon stimulation by about 50%. Interestingly, high circulating PMN-MDSC numbers were associated with lymphocytopenia. The number of circulating regulatory T cells (Treg) and monocytic MDSC (M-MDSC) showed no significant parasitemia-dependent variation. These results highlight PMN-MDSC in the peripheral circulation as an early indicator of infection during malaria. They suppress CD4+ and CD8+ T cell proliferation in vitro. Their contribution to immunosuppression in vivo in subclinical and uncomplicated malaria will be the subject of further research. Pre-emptive antimalarial pre-treatment of vaccinees to reverse malaria-associated PMN-MDSC immunosuppression could improve vaccine response in exposed individuals.

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Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells

Blood ◽

10.1182/blood-2006-02-002246 ◽

2006 ◽

Vol 109 (1) ◽

pp. 228-234 ◽

Cited By ~ 596

Author(s):

Kazuya Sato ◽

Katsutoshi Ozaki ◽

Iekuni Oh ◽

Akiko Meguro ◽

Keiko Hatanaka ◽

...

Keyword(s):

Nitric Oxide ◽

Stem Cells ◽

Cell Proliferation ◽

T Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Molecular Mechanisms ◽

Critical Role ◽

Specific Inhibitor ◽

T Cell Proliferation

Abstract The molecular mechanisms by which mesenchymal stem cells (MSCs) suppress T-cell proliferation are poorly understood, and whether a soluble factor plays a major role remains controversial. Here we demonstrate that the T-cell–receptor complex is not a target for the suppression, suggesting that downstream signals mediate the suppression. We found that Stat5 phosphorylation in T cells is suppressed in the presence of MSCs and that nitric oxide (NO) is involved in the suppression of Stat5 phosphorylation and T-cell proliferation. The induction of inducible NO synthase (NOS) was readily detected in MSCs but not T cells, and a specific inhibitor of NOS reversed the suppression of Stat5 phosphorylation and T-cell proliferation. This production of NO in the presence of MSCs was mediated by CD4 or CD8 T cells but not by CD19 B cells. Furthermore, inhibitors of prostaglandin synthase or NOS restored the proliferation of T cells, whereas an inhibitor of indoleamine 2,3-dioxygenase and a transforming growth factor–β–neutralizing antibody had no effect. Finally, MSCs from inducible NOS−/− mice had a reduced ability to suppress T-cell proliferation. Taken together, these results suggest that NO produced by MSCs is one of the major mediators of T-cell suppression by MSCs.

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