CD85k Contributes to Regulatory T Cell Function in Chronic Viral Infections

Regulatory T cells (Tregs) prevent excessive immune responses and limit immune pathology upon infections. To fulfill this role in different immune environments elicited by different types of pathogens, Tregs undergo functional specialization into distinct subsets. During acute type 1 immune responses, type 1 Tregs are induced and recruited to the site of ongoing Th1 responses to efficiently control Th1 responses. However, whether a similar specialization process also takes place following chronic infections is still unknown. In this study, we investigated Treg specialization in persistent viral infections using lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV) infection as models for chronic and latent infections, respectively. We identify CD85k as a Th1-specific co-inhibitory receptor with sustained expression in persistent viral infections and show that recombinant CD85k inhibits LCMV-specific effector T cells. Furthermore, expression of the CD85k ligand ALCAM is induced on LCMV-specific and exhausted T cells during chronic LCMV infection. Finally, we demonstrate that type 1 Tregs arising during chronic LCMV infection suppress Th1 effector cells in an ALCAM-dependent manner. These results extend the current knowledge of Treg specialization from acute to persistent viral infections and reveal an important functional role of CD85k in Treg-mediated suppression of type 1 immunity.

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MECHANISMS IN ENDOCRINOLOGY: Insulin and type 1 diabetes: immune connections

Acta Endocrinologica ◽

10.1530/eje-12-0693 ◽

2013 ◽

Vol 168 (2) ◽

pp. R19-R31 ◽

Cited By ~ 15

Author(s):

Sloboda Culina ◽

Vedran Brezar ◽

Roberto Mallone

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Immune Responses ◽

Current Knowledge ◽

Target Antigen ◽

Β Cells ◽

Autoreactive T Cells ◽

Central Tolerance ◽

Initial Target

Insulin is the hormone produced by pancreatic β-cells, with a central role in carbohydrate and fat metabolism. Together with its precursors preproinsulin and proinsulin, insulin is also a key target antigen (Ag) of the autoimmune islet destruction leading to type 1 diabetes. Being recognized by both autoantibodies (aAbs) and autoreactive T cells, insulin plays a triggering role, at least in rodent models, in diabetes pathogenesis. It is expressed not only by β-cells but also in the thymus, where it plays a major role in central tolerance mechanisms. We will summarize current knowledge concerning insulin, its role in β-cell autoimmunity as initial target Ag, its recognition by aAbs and autoreactive T cells, and the detection of these immune responses to provide biomarkers for clinical trials employing insulin as an immune modulatory agent.

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Chronic virus infection compromises memory bystander T cell function in an IL-6/STAT1-dependent manner

Journal of Experimental Medicine ◽

10.1084/jem.20181589 ◽

2019 ◽

Vol 216 (3) ◽

pp. 571-586 ◽

Cited By ~ 5

Author(s):

Isabel Barnstorf ◽

Mariana Borsa ◽

Nicolas Baumann ◽

Katharina Pallmer ◽

Alexander Yermanos ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virus Infection ◽

Cd8 T Cells ◽

Viral Infections ◽

Dependent Manner ◽

Chronic Viral Infections ◽

And Function ◽

The Impact ◽

Lcmv Infection

Chronic viral infections are widespread among humans, with ∼8–12 chronic viral infections per individual, and there is epidemiological proof that these impair heterologous immunity. We studied the impact of chronic LCMV infection on the phenotype and function of memory bystander CD8+ T cells. Active chronic LCMV infection had a profound effect on total numbers, phenotype, and function of memory bystander T cells in mice. The phenotypic changes included up-regulation of markers commonly associated with effector and exhausted cells and were induced by IL-6 in a STAT1-dependent manner in the context of chronic virus infection. Furthermore, bystander CD8 T cell functions were reduced with respect to their ability to produce inflammatory cytokines and to undergo secondary expansion upon cognate antigen challenge with major cell-extrinsic contributions responsible for the diminished memory potential of bystander CD8+ T cells. These findings open new perspectives for immunity and vaccination during chronic viral infections.

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Immune Responses Against Persistent Viral Infections: Possible Avenues for Immunotherapeutic Interventions

Critical Reviews™ in Immunology ◽

10.1615/critrevimmunol.v28.i2.40 ◽

2008 ◽

Vol 28 (2) ◽

pp. 159-183 ◽

Cited By ~ 24

Author(s):

Shinichiro Fuse ◽

Michael J. Molloy ◽

Edward J. Usherwood

Keyword(s):

Immune Responses ◽

Viral Infections ◽

Persistent Viral Infections

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The Role of Human T-Lymphotropic Virus Type 1 (HTLV-1)-Infected Dendritic Cells in the Development of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

Journal of Virology ◽

10.1128/jvi.73.6.4575-4581.1999 ◽

1999 ◽

Vol 73 (6) ◽

pp. 4575-4581 ◽

Cited By ~ 61

Author(s):

Masahiko Makino ◽

Satoshi Shimokubo ◽

Shin-Ichi Wakamatsu ◽

Shuji Izumo ◽

Masanori Baba

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Virus Type ◽

Spastic Paraparesis ◽

Tropical Spastic Paraparesis ◽

Normal Donor ◽

Dependent Manner ◽

T Lymphotropic Virus

ABSTRACT The development of human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is closely associated with the activation of T cells which are HTLV-1 specific but may cross-react with neural antigens (Ags). Immature dendritic cells (DCs), differentiated from normal donor monocytes by using recombinant granulocyte-macrophage colony-stimulating factor and recombinant interleukin-4, were pulsed with HTLV-1 in vitro. The pulsed DCs contained HTLV-1 proviral DNA and expressed HTLV-1 Gag Ag on their surface 6 days after infection. The DCs matured by lipopolysaccharides stimulated autologous CD4+ T cells and CD8+ T cells in a viral dose-dependent manner. However, the proliferation level of CD4+ T cells was five- to sixfold higher than that of CD8+ T cells. In contrast to virus-infected DCs, DCs pulsed with heat-inactivated virions activated only CD4+ T cells. To clarify the role of DCs in HAM/TSP development, monocytes from patients were cultured for 4 days in the presence of the cytokines. The expression of CD86 Ag on DCs was higher and that of CD1a Ag was more down-regulated than in DCs generated from normal monocytes. DCs from two of five patients expressed HTLV-1 Gag Ag. Furthermore, both CD4+ and CD8+ T cells from the patients were greatly stimulated by contact with autologous DCs pulsed with inactivated viral Ag as well as HTLV-1-infected DCs. These results suggest that DCs are susceptible to HTLV-1 infection and that their cognate interaction with T cells may contribute to the development of HAM/TSP.

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Interferon-γ-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell

Blood ◽

10.1182/blood-2005-07-2793 ◽

2006 ◽

Vol 107 (6) ◽

pp. 2570-2577 ◽

Cited By ~ 221

Author(s):

John Stagg ◽

Sandra Pommey ◽

Nicoletta Eliopoulos ◽

Jacques Galipeau

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Stromal Cells ◽

Matrix Protein ◽

Marrow Stromal Cells ◽

Human Mscs ◽

Dependent Manner ◽

Antigen Presenting ◽

Significant Production

AbstractSeveral studies have demonstrated that marrow stromal cells (MSCs) can suppress allogeneic T-cell responses. However, the effect of MSCs on syngeneic immune responses has been largely overlooked. We describe here that primary MSCs derived from C57BL/6 mice behave as conditional antigen-presenting cells (APCs) and can induce antigen-specific protective immunity. Interferon gamma (IFNγ)-treated C57BL/6 MSCs, but not unstimulated MSCs, cocultured with ovalbumin-specific major histocompatibility (MHC) class II-restricted hybridomas in the presence of soluble ovalbumin-induced significant production of interleukin-2 (IL-2) in an antigen dose-dependent manner (P < .005). IFNγ-treated MSCs could further activate in vitro ovalbumin-specific primary transgenic CD4+ T cells. C57BL/6 MSCs, however, were unable to induce antigen cross-presentation via the MHC class I pathway. When syngeneic mice were immunized intraperitoneally with ovalbumin-pulsed IFNγ-treated MSCs, they developed antigen-specific cytotoxic CD8+ T cells and became fully protected (10 of 10 mice) against ovalbumin-expressing E.G7 tumors. Human MSCs were also studied for antigen-presenting functions. IFNγ-treated DR1-positive human MSCs, but not unstimulated human MSCs, induced significant production of IL-2 when cocultured with DR1-restricted influenza-specific humanized T-cell hybridomas in the presence of purified influenza matrix protein 1. Taken together, our data strongly suggest that MSCs behave as conditional APCs in syngeneic immune responses. (Blood. 2006;107:2570-2577)

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Differential Activation of CD8+Tumor-Specific Tc1 and Tc2 Cells by an IL-10-Producing Murine Plasmacytoma

Developmental Immunology ◽

10.1155/1998/93545 ◽

1998 ◽

Vol 6 (3-4) ◽

pp. 331-342 ◽

Cited By ~ 1

Author(s):

Christoph Specht ◽

Hans-Gerd Pauels ◽

Christian Becker ◽

Eckehart Kölsch

Keyword(s):

T Cells ◽

Immune Responses ◽

Tumor Cells ◽

T Cell Subsets ◽

Early Stages ◽

Specific Tolerance

The involvement of counteractiveCD8+T-cell subsets during tumor-specific immune responses was analyzed in a syngeneic murine plasmacytoma model.CD8+Tc cells against the immunogenic IL-10-producing BALB/c plasmacytoma ADJ-PC-5 can be easily induced by immunization of BALB/c mice with X-irradiated ADJ-PC-5 tumor cellsin vivoandin vitro. However, the failure of recipient mice to mount a protective Tc response against the tumor during early stages of a real or simulated tumor growth is not due to immunological ignorance, but depends on the induction of tumor-specific tolerance, involving a population of tumorinducedCD8+T cells that are able to inhibit the generation of tumor-specific Tc cells in a primary ADJ-PC-5-specific MLTC, using IFN-γas a suppressive factor. Whereas most longterm cultivated CD8+ADJ-PC-5-specific Tc lines produce type-1 cytokines on stimulation, at least two of them, which were derived from a primary MLTC, display a type-2 cytokine spectrum. Furthermore, the primaryin vitroTc response against ADJ-PC-5 cells shows characteristics of a Tc2 response. The Tc response is strictly depending on tumor-derived IL-10.CD8+Tc cells that are induced in a primary MLTC do not produce IFN-γ, and the tumor-specific Tc response is enhanced by IL-4 but suppressed by IFN-γor IL-12. In contrast, ADJ-PC- 5-specificCD8+Tc cells from immunized mice are IFN-γproducing Tc1 cells. Since the primaryin vitroTc response against the tumor is suppressed even by the smallest numbers of irradiated ADJ-PC-5-specific Tc1 cells via IFN-γthese Tc1 cells behave similar to the suppressiveCD8+T cells that are induced during early stages of ADJ-PC-5 tumorigenesis.

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Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

Journal of Virology ◽

10.1128/jvi.79.15.9419-9429.2005 ◽

2005 ◽

Vol 79 (15) ◽

pp. 9419-9429 ◽

Cited By ~ 29

Author(s):

Nicole E. Miller ◽

Jennifer R. Bonczyk ◽

Yumi Nakayama ◽

M. Suresh

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Response ◽

Viral Infections ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Cell Responses ◽

Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

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Human Dendritic Cells: Ontogeny and Their Subsets in Health and Disease

Medical Sciences ◽

10.3390/medsci6040088 ◽

2018 ◽

Vol 6 (4) ◽

pp. 88 ◽

Cited By ~ 8

Author(s):

Sandra Solano-Gálvez ◽

Sonia Tovar-Torres ◽

María Tron-Gómez ◽

Ariane Weiser-Smeke ◽

Diego Álvarez-Hernández ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune Responses ◽

Cd8 T Cells ◽

Current Knowledge ◽

Lymphoid Organ ◽

Heterogeneous Population ◽

Health And Disease ◽

Human Dendritic Cells ◽

Activation Status

Dendritic cells (DCs) are a type of cells derived from bone marrow that represent 1% or less of the total hematopoietic cells of any lymphoid organ or of the total cell count of the blood or epithelia. Dendritic cells comprise a heterogeneous population of cells localized in different tissues where they act as sentinels continuously capturing antigens to present them to T cells. Dendritic cells are uniquely capable of attracting and activating naïve CD4+ and CD8+ T cells to initiate and modulate primary immune responses. They have the ability to coordinate tolerance or immunity depending on their activation status, which is why they are also considered as the orchestrating cells of the immune response. The purpose of this review is to provide a general overview of the current knowledge on ontogeny and subsets of human dendritic cells as well as their function and different biological roles.

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The activation of bystander CD8+ T cells and their roles in viral infection

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0316-1 ◽

2019 ◽

Vol 51 (12) ◽

pp. 1-9 ◽

Cited By ~ 12

Author(s):

Tae-Shin Kim ◽

Eui-Cheol Shin

Keyword(s):

T Cells ◽

Viral Infections ◽

Hepatitis A Virus ◽

Tissue Injury ◽

Strong Association ◽

Killer Cell ◽

Type I Interferons ◽

Type I ◽

Dependent Manner ◽

Bystander Activation

AbstractDuring viral infections, significant numbers of T cells are activated in a T cell receptor-independent and cytokine-dependent manner, a phenomenon referred to as “bystander activation.” Cytokines, including type I interferons, interleukin-18, and interleukin-15, are the most important factors that induce bystander activation of T cells, each of which plays a somewhat different role. Bystander T cells lack specificity for the pathogen, but can nevertheless impact the course of the immune response to the infection. For example, bystander-activated CD8+ T cells can participate in protective immunity by secreting cytokines, such as interferon-γ. They also mediate host injury by exerting cytotoxicity that is facilitated by natural killer cell-activating receptors, such as NKG2D, and cytolytic molecules, such as granzyme B. Interestingly, it has been recently reported that there is a strong association between the cytolytic function of bystander-activated CD8+ T cells and host tissue injury in patients with acute hepatitis A virus infection. The current review addresses the induction of bystander CD8+ T cells, their effector functions, and their potential roles in immunity to infection, immunopathology, and autoimmunity.

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