Abstract 155: Sustained CD4+ T-Cell Activation Promotes Transplant-Associated Recipient Cardiovascular Disease

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in transplant patients. The mechanisms underlying increased recipient CVD are poorly understood. We have established an animal model of transplant-associated recipient CVD by combining murine models of atherosclerosis (apolipoprotein E-deficient recipients, ApoE -/- ) and of transplant rejection (heterotopic cardiac transplantation). Mice were placed on a normal chow diet for 3 months after transplantation and then analyzed. ApoE -/- recipients of rejecting allografts developed more severe aortic atherosclerosis compared to syngeneic controls, most strikingly across a major histocompatibility complex (MHC) class II antigen barrier (Fig. A). Atherosclerotic lesions were associated with increased CD4 + T cell infiltration and sustained CD4 + T cell activation as assessed by flow cytometry. Total cholesterol and triglyceride levels were unchanged. Cardiac function and aortic distention by echocardiography demonstrated significant impairment in recipients of MHC class II mismatched grafts (Fig. B). In addition, quantitative assessment of proinflammatory cytokines demonstrated significantly elevated plasma levels of interferon (IFN)-γ, the signature Th1 cytokine, as well as IFN-γ inducer cytokine IL-12 in mice with MHC class II mismatched grafts. Our study provides an experimental model of transplant-associated recipient CVD, reveals the critical role of sustained CD4 + T cell activation by donor-recipient immunological crosstalk, and has the potential for identifying novel therapeutic interventions for transplant-associated recipient CVD.

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Involvement of both major histocompatibility complex class II alpha and beta chains in CD4 function indicates a role for ordered oligomerization in T cell activation.

Journal of Experimental Medicine ◽

10.1084/jem.182.3.779 ◽

1995 ◽

Vol 182 (3) ◽

pp. 779-787 ◽

Cited By ~ 85

Author(s):

R König ◽

X Shen ◽

R N Germain

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

T Cell Activation ◽

Cell Activation ◽

Critical Role ◽

Class Ii ◽

Specific Receptor ◽

Single Class ◽

Histocompatibility Complex ◽

Beta 2

CD4 is a membrane glycoprotein on T lymphocytes that binds to the same peptide:major histocompatibility complex (MHC) class II molecule recognized by the antigen-specific receptor (TCR), thereby stabilizing interactions between the TCR and peptide;MHC class II complexes and promoting the localization of the src family tyrosine kinase p56lck into the receptor complex. Previous studies identified a solvent-exposed loop on the class II beta 2 domain necessary for binding to CD4 and for eliciting CD4 coreceptor activity. Here, we demonstrate that a second surface-exposed segment of class II is also critical for CD4 function. This site is in the alpha 2 domain, positioned in single class II heterodimers in such a way that it cannot simultaneously interact with the same CD4 molecule as the beta 2 site. The ability of mutations at either site to diminish CD4 function therefore indicates that specifically organized CD4 and/or MHC class II oligomers play a critical role in coreceptor-dependent T cell activation.

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Activation of Human T Cells by Major Histocompatability Complex Class II Expressing Neutrophils: Proliferation in the Presence of Superantigen, But Not Tetanus Toxoid

Blood ◽

10.1182/blood.v89.11.4128 ◽

1997 ◽

Vol 89 (11) ◽

pp. 4128-4135 ◽

Cited By ~ 89

Author(s):

Neil A. Fanger ◽

Chunlei Liu ◽

Paul M. Guyre ◽

Kathleen Wardwell ◽

Jerome O'Neil ◽

...

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

T Cell Activation ◽

Tetanus Toxoid ◽

Cell Activation ◽

Class Ii ◽

Polymorphonuclear Neutrophils ◽

Gm Csf ◽

Ifn Γ ◽

Mhc Class Ii Molecules

Abstract The primary function of polymorphonuclear neutrophils (PMN) in the immune response appears to be acute phagocytic clearance of foreign pathogens and release of inflammatory mediators. Consistent with their assumed lack of major histocompatibility complex (MHC) class II expression, PMN have not been considered to play a role in antigen presentation and T-cell activation. However, recent reports have shown that human PMN can express MHC class II molecules both in vitro and in vivo after stimulation with either granulocyte-macrophage colony-stimulating factor (GM-CSF ) or interferon-γ (IFN-γ). Thus, under appropriate conditions, PMN could play a significant role in immune regulation, including T-cell activation. In this report, we demonstrate that human class II–expressing PMN can serve as accessory cells in superantigen (SAg)-mediated T-cell activation. This accessory activity for SAg presentation was present only after induction of MHC class II expression, and was especially pronounced following culture of PMN with GM-CSF plus IFN-γ, which acted synergistically to induce MHC class II molecules on PMN. Moreover, the level of MHC class II expression and the magnitude of SAg-induced T-cell responses were found to be highly correlated and distinctly donor dependent, with PMN from some donors repeatedly showing fivefold higher responses than PMN from other donors. On the other hand, culture of PMN with GM-CSF plus IFN-γ under conditions that resulted in optimal MHC class II expression did not enable them to function as antigen-presenting cells for either intact tetanus toxoid (TT) or for a TT peptide. These results delineate a new pathway for T-cell activation by SAg that may play an important role in the severity of SAg-induced inflammatory responses. They also identify a donor-specific polymorphism for induction of PMN MHC class II expression which may be of significance for therapies involving GM-CSF and IFN-γ.

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Inducible MHC Class II Expression by Mast Cells Supports Effector and Regulatory T Cell Activation

The Journal of Immunology ◽

10.4049/jimmunol.0803180 ◽

2009 ◽

Vol 182 (8) ◽

pp. 4686-4695 ◽

Cited By ~ 96

Author(s):

Taku Kambayashi ◽

Eric J. Allenspach ◽

John T. Chang ◽

Tao Zou ◽

Jonathan E. Shoag ◽

...

Keyword(s):

T Cell ◽

Mast Cells ◽

Mhc Class Ii ◽

T Cell Activation ◽

Regulatory T Cell ◽

Cell Activation ◽

Class Ii

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H2-M and H2-O as Targeting Vehicles for the MHC Class II Processing Compartment Promote Antigen-Specific CD4+ T Cell Activation

Vaccines ◽

10.3390/vaccines9101053 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1053

Author(s):

Lucia Lapazio ◽

Monika Braun ◽

Kaj Grandien

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

T Cell Activation ◽

Cell Activation ◽

Class Ii ◽

Cd4 T Cell ◽

Antigen Presentation Pathway ◽

Presentation Pathway ◽

Class Ii Antigen ◽

Mhc Class Ii Antigen

CD8 and CD4 T cell activation are both required for a strong and long-lasting T cell immune response. Endogenously expressed proteins are readily processed by the MHC class I antigen presentation pathway, enabling activation of CD8+ T cells. However, the MHC class II antigen presentation pathway, necessary for CD4+ T cell activation, is generally not sufficiently accessible to endogenously expressed proteins, limiting the efficiency of mRNA- or DNA-based vaccines. In the current study, we have evaluated the feasibility of using antigen sequences fused to sequences derived from the H2-M and H2-O proteins, two complexes known to participate in MHC class II antigen processing, for the enhancement of CD4 T-cell activation. We analyzed T cell activation after genetic immunization with mRNA-encoding fusion proteins with the model antigen ovalbumin and sequences derived from H2-M or H2-O. Our results show that H2-M- or H2-O-derived sequences robustly improve antigen-specific CD4 T-cell activation when fused to the antigen of interest and suggest that the approach could be used to improve the efficiency of mRNA- or DNA-based vaccines.

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MHC Class II Ir/Is Gene Controlled Antigen Specific T Cell Activation and Disease Susceptibility: Leprosy, a Human Model

Recognition of M. leprae antigens ◽

10.1007/978-94-009-3327-9_2 ◽

1987 ◽

pp. 12-51

Author(s):

Tom Ottenhoff ◽

René de Vries

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

T Cell Activation ◽

Cell Activation ◽

Disease Susceptibility ◽

Class Ii ◽

Human Model

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Nontoxic Shiga Toxin Derivatives from Escherichia coli Possess Adjuvant Activity for the Augmentation of Antigen-Specific Immune Responses via Dendritic Cell Activation

Infection and Immunity ◽

10.1128/iai.73.7.4088-4097.2005 ◽

2005 ◽

Vol 73 (7) ◽

pp. 4088-4097 ◽

Cited By ~ 24

Author(s):

Mari Ohmura ◽

Masafumi Yamamoto ◽

Chikako Tomiyama-Miyaji ◽

Yoshikazu Yuki ◽

Yoshifumi Takeda ◽

...

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

Shiga Toxin ◽

Cell Activation ◽

Class Ii ◽

Immunoglobulin M ◽

Interleukin 12 ◽

Adjuvant Activity ◽

Ifn Γ ◽

Th1 And Th2

ABSTRACT Shiga toxin (Stx) derivatives, such as the Stx1 B subunit (StxB1), which mediates toxin binding to the membrane, and mutant Stx1 (mStx1), which is a nontoxic doubly mutated Stx1 harboring amino acid substitutions in the A subunit, possess adjuvant activity via the activation of dendritic cells (DCs). Our results showed that StxB1 and mStx1, but not native Stx1 (nStx1), resulted in enhanced expression of CD86, CD40, and major histocompatibility complex (MHC) class II molecules and, to some extent, also enhanced the expression of CD80 on bone marrow-derived DCs. StxB1-treated DCs exhibited an increase in tumor necrosis factor alpha and interleukin-12 (IL-12) production, a stimulation of DO11.10 T-cell proliferation, and the production of both Th1 and Th2 cytokines, including gamma interferon (IFN-γ), IL-4, IL-5, IL-6, and IL-10. When mice were given StxB1 subcutaneously, the levels of CD80, CD86, and CD40, as well as MHC class II expression by splenic DCs, were enhanced. The subcutaneous immunization of mice with ovalbumin (OVA) plus mStx1 or StxB1 induced high titers of OVA-specific immunoglobulin M (IgM), IgG1, and IgG2a in serum. OVA-specific CD4+ T cells isolated from mice immunized with OVA plus mStx1 or StxB1 produced IFN-γ, IL-4, IL-5, IL-6, and IL-10, indicating that mStx1 and StxB1 elicit both Th1- and Th2-type responses. Importantly, mice immunized subcutaneously with tetanus toxoid plus mStx1 or StxB1 were protected from a lethal challenge with tetanus toxin. These results suggest that nontoxic Stx derivatives, including both StxB1 and mStx1, could be effective adjuvants for the induction of mixed Th-type CD4+ T-cell-mediated antigen-specific antibody responses via the activation of DCs.

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Selective immunosuppression by administration of major histocompatibility complex (MHC) class II-binding peptides. I. Evidence for in vivo MHC blockade preventing T cell activation.

Journal of Experimental Medicine ◽

10.1084/jem.175.5.1345 ◽

1992 ◽

Vol 175 (5) ◽

pp. 1345-1352 ◽

Cited By ~ 30

Author(s):

J C Guéry ◽

A Sette ◽

J Leighton ◽

A Dragomir ◽

L Adorini

Keyword(s):

T Cells ◽

T Cell ◽

Antigen Presentation ◽

Mhc Class Ii ◽

T Cell Activation ◽

Cell Activation ◽

Class Ii ◽

Specific Class ◽

Binding Peptide

Draining lymph node cells (LNC) from mice immunized with hen egg white lysozyme (HEL) display at their surface antigen-MHC complexes able to stimulate, in the absence of any further antigen addition, HEL peptide-specific, class II-restricted T cell hybridomas. Chloroquine addition to these LNC cultures fails to inhibit antigen presentation, indicating that antigenic complexes of class II molecules and HEL peptides are formed in vivo. MHC class II restriction of antigen presentation by LNC from HEL-primed mice was verified by the use of anti-class II monoclonal antibodies. Coinjection of HEL and the I-Ak-binding peptide HEL 112-129 in mice of H-2k haplotype inhibits the ability of LNC to stimulate I-Ak-restricted, HEL 46-61-specific T cell hybridomas. Similar results are obtained in mice coinjected with the HEL peptides 46-61 and 112-129. Inhibition of T hybridoma activation can also be observed using as antigen-presenting cells irradiated, T cell-depleted LNC from mice coinjected with HEL 46-61 and HEL 112-129, ruling out the possible role of either specific or nonspecific suppressor T cells. Inhibition of T cell proliferation is associated with MHC-specific inhibition of antigen presentation and with occupancy by the competitor of class II binding sites, as measured by activation of peptide-specific T cell hybridomas. These results demonstrate that administration of MHC class II binding peptide competitors selectively inhibits antigen presentation to class II-restricted T cells, indicating competitive blockade of class II molecules in vivo.

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Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation

Blood ◽

10.1182/blood-2011-06-363994 ◽

2012 ◽

Vol 119 (1) ◽

pp. 127-136 ◽

Cited By ~ 42

Author(s):

Min Chen ◽

Kumar Felix ◽

Jin Wang

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Inflammatory Responses ◽

Critical Role ◽

Cell Types ◽

Activated T Cells ◽

Ifn Γ

AbstractAfter stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be determined. Here we show that perforin deficiency in mice, together with the deletion of Fas in DCs (perforin−/−DC-Fas−/−), led to DC accumulation, uncontrolled T-cell activation, and IFN-γ production by CD8+ T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas−/− DCs induced over-activation and IFN-γ production in perforin−/− CD8+ T cells. Neutralization of IFN-γ prevented the spreading of inflammatory responses to different cell types and protected the survival of perforin−/−DC-Fas−/− mice. Our data suggest that perforin and Fas synergize in the maintenance of DC homeostasis to limit T cell activation, and prevent the initiation of an inflammatory cascade.

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