4-1BB costimulation enhances HSV-1-specific CD8+ T cell responses by the induction of CD11c+CD8+ T cells

doi:10.1016/j.cellimm.2006.01.004

Cellular Immunology

Volume 238, Issue 2, December 2005, Pages 76-86

https://doi.org/10.1016/j.cellimm.2006.01.004 Get rights and content

Abstract

Since 4-1BB plays a predominant role in CD8⁺ T cell responses, we investigated the effects of 4-1BB triggering on the primary and memory CD8⁺ T responses to HSV-1 infection. 4-1BB was detected on 10–15% of CD4⁺ and CD8⁺ T cells following the infection. 4-1BB-positive T cells were in the proliferative mode and showed the enhanced expression of anti-apoptotic proteins. Agonistic anti-4-1BB treatment exerted preferential expansion of CD8⁺ T cells and gB/H-2K^b-positive CD8⁺ T cells, and enhanced cytotoxicity against HSV-1 that was mainly mediated by CD11c⁺CD8⁺ T cells. CD11c⁺CD8⁺ T cells were re-expanded following re-challenge with HSV-1 at post-infection day 50, indicating that CD11c⁺CD8⁺ phenotype was maintained in memory CD8⁺ T cell pool. Our studies demonstrated that 4-1BB stimulation enhanced both primary and memory anti-HSV-1 CD8⁺ T cell responses, which was mediated by a massive expansion of antigen-specific CD11c⁺CD8⁺ T cells.

Introduction

Herpes simplex virus type 1 (HSV-1)¹ infects and causes disease in epidermal or mucosal tissues. The virus also travels to the neural ganglia via retrograde axonal flow, where persists in a latent state throughout the life of the host. Periodically, the latent virus may reactivate and cause recurrent lesions at or near the initial site of infection [1].

A rapid and specific response from the adaptive immune system is essential to overcome the rapidly replicating virus [2]. The clearance of acute cutaneous HSV-1 infection depends on T cell-mediated immune functions in humans [3], [4] and experimental murine models [5]; in particular, CD8⁺ T cells are protective against various forms of HSV-1 infection [6], [7].

4-1BB, an inducible T cell surface receptor on CD4⁺, CD8⁺, NK 1.1, and dendritic cells, provides CD28-independent costimulation of T cell activation [8], [9], [10]. 4-1BB-mediated signaling plays a critical role in preventing activation-induced cell death, promoting the rejection of cardiac allografts and skin transplants, enhancing integrin-mediated cell adhesion, and increasing T cell cytolytic potential [8], [10], [11], as well as in eradicating established tumors [10], [12], [13], [14]. 4-1BB-deficient mice have normal T and B cell numbers but have defects in antigen-specific IFN-γ expression and CTL activity [15].

A previous report has shown that in vivo 4-1BB stimulation with an agonistic monoclonal antibody could enhance and broaden the primary CD8⁺ T cell response to influenza type A viral infection in mice [16]. In the present study, we have tested whether in vivo 4-1BB stimulation could also enhance the effector functions of HSV-1-specific CD8⁺ T cells in primary and secondary immune responses.

Section snippets

Mice, virus, and peptide

Six- to eight-week-old C57BL/6 mice were purchased from the Halran Laboratories (Indianapolis, IN). 4-1BB^−/− (H-2K^b) C57BL/6 mice were bred in a specific pathogen-free facility at the University of Ulsan, Ulsan, Korea. The HSV-1 KOS strain was grown on CV-1 cells in minimal essential media (MEM)—10% FBS, penicillin (100 U/ml), and streptomycin (100 μg/ml). Virus was titered on CV-1 cells by plaque assay. Virus was aliquoted in 1-ml vials and stored at −70 °C till use. The gB_498–505 peptide

Characterization of 4-1BB-expressing CD4⁺ and CD8⁺ T cells after HSV-1 infection

Previous studies have reported that 4-1BB plays an important role in the effector function of antigen-specific CD8⁺ T cells [16]. We examined the expression kinetics of 4-1BB on CD4⁺ and CD8⁺ T cells after the HSV-1 infection. 4-1BB expression on CD4⁺ and CD8⁺ T cells peaked on PI day 2 following HSV-1 footpad infection (12.73 ± 3.2% of total DLN CD4⁺ T cells; 11.79 ± 3.0% of total DLN CD8⁺ T cells), and decreased thereafter (Fig. 1A). The 4-1BB expression was almost at the basal level by PI day 5.

Discussion

We found that CD4⁺ T and CD8⁺ T cells express similar levels of 4-1BB on their surfaces after HSV-1 infection, and that the expression of 4-1BB appears to protect CD4⁺ and CD8⁺ T cells from apoptosis as a result of increased Bcl-2 and Bcl-x_L (Fig. 1B). Nevertheless, anti-4-1BB stimulation greatly enhanced the proliferation of CD8⁺ T cell response (10- to 12-fold), whereas proliferation of CD4⁺ T cells was less marked (2- to 3-fold) (Fig. 2A).

At the peak of 4-1BB expression (PI day 2), 10–15% of

Acknowledgments

This research was supported by NIH Grants R01EY013325 (B.S.K.) and P30EY002377 (LSU Eye Center Core grant), KRF-2005-084-E00001, KRF-2005-201-E00008, Korea Health 21 R&D, A050260 and the SRC Fund to the IRC at University of Ulsan from KOSEF and the Korean Ministry of Science and Technology.

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4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T cells in a CD40-dependent manner

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Recently Naradikian and colleagues demonstrated that some memory B cells also express CD11c due to a unique cytokine milieu and/or infections [52]. With regard to murine T cells CD11b expression correlates with their level of activity [41] and is often co-expressed with CD11c on activated T cells [42,43,45]. A number of studies revealed, that only activated T cells express CD11c [42–45].
Integrins are cell membrane receptors that are involved in essential physiological and serious pathological processes. Their main role is to ensure a closely regulated link between the extracellular matrix and the intracellular cytoskeletal network enabling cells to react to environmental stimuli. Complement receptor type 3 (CR3, αMβ₂, CD11b/CD18) and type 4 (CR4, αXβ₂, CD11c/CD18) are members of the β₂-integrin family expressed on most white blood cells. Both receptors bind multiple ligands like iC3b, ICAM, fibrinogen or LPS. β₂-integrins are accepted to play important roles in cellular adhesion, migration, phagocytosis, ECM rearrangement and inflammation. Several pathological conditions are linked to the impaired functions of these receptors.
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It was not clear from the above study whether these cells directly mediate virus clearance or act in a bystander fashion. This issue was addressed recently by the study of Kim et al. [30] who demonstrated that when HSV-1-infected mice are treated with anti-4-1BB numbers of IFN-γ-producing CD11c+CD8+ T cells increase. The increased IFN-γ in turn enhances the anti-viral properties of conventional CTLs [30], suggesting that the CD11c+CD8+ T cells act as supporters of CTLs in this model.
Regulatory cells, important controllers of immune homeostasis, carry out a multi-pronged attack by deleting overactive pathogenic immune cells, by supporting anergy, and by blocking effector functions, thereby contributing to the amelioration of disease. CD8⁺ T cells co-expressing CD11c are a new addition to the growing list of regulatory cells. Naïve mice harbor CD11c-expressing CD8⁺ T cells (<3%) that expand further in an antigen-dependent manner. Although activated CD11c⁺CD8⁺ T cells express suppressive cytokines such as IL-10 and TGF-β, their production of IFN-γ is central to their immune suppressive potential. The CD11c⁺CD8⁺ T cells target pathogenic CD4⁺ T cells in a cell–cell contact dependent manner via IDO- and GCN2-dependent mechanisms. Adoptive transfer of activated CD11c⁺CD8⁺ T cells halts the progression of autoimmune rheumatoid arthritis and colitis. However, in certain virus and cancer models the CD11c⁺CD8⁺ T cells assume the role of immune effectors, boosting immune potential. This seemingly dual nature of these cells – exerting regulatory vs. effector activities – makes them an attractive therapeutic target. In this review, we discuss the discovery, origins and developmental requirements of CD11c⁺CD8⁺cells, and the basis of their immuno-suppressive and effector potentials.
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The TNFR family members OX40 (CD134) and 4-1BB (CD137) have been found to play major roles as costimulatory receptors for both CD4 and CD8 T cells. In particular, in many situations, they can control proliferation, survival, and cytokine production, and hence are thought to dictate accumulation of protective T cells during anti-viral and anti-tumor responses and pathogenic T cells during autoimmune reactions. As opposed to simply controlling the activity of naïve, effector, and memory T cells, recent data have suggested that both molecules are also instrumental in controlling the generation and activity of so-called regulatory or suppressor T cells (Treg), perhaps in both positive and negative manners. Part of the action on Treg might function to further promote protective or pathogenic T cells, but alternate activities of OX40 and 4-1BB on Treg are also being described that suggest that there might be control by these molecules at multiple levels that will alter the biological outcome when these receptors are ligated. This review specifically focuses on recent studies of regulatory T cells, and regulatory or suppressive activity, that are modulated by OX40 or 4-1BB.
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Cellular Immunology

Abstract

Introduction

Section snippets

Mice, virus, and peptide

Characterization of 4-1BB-expressing CD4⁺ and CD8⁺ T cells after HSV-1 infection

Discussion

Acknowledgments

References (24)

Control of acute cutaneous herpes simplex virus infection: T cell-mediated viral clearance is dependent upon interferon-γ (IFN-γ)

Virology

NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies

Cell Immunol.

Herpes simplex virus-specific CD8⁺ T cells can clear established lytic infections from skin and nerves and can partially limit the early spread of virus after cutaneous inoculation

J. Immunol.

Rapid cytotoxic T lymphocyte activation occurs in the draining lymph nodes after cutaneous herpes simplex virus infection as a result of early antigen presentation and not the presence of virus

J. Exp. Med.

Herpes simplex viruses

In Fundamental Immunology

Different roles for L3T4⁺ and Lyt 2⁺ T cell subsets in the control of an acute herpes simplex virus infection of the skin and nervous system

J. Gen. Virol.

Anti-CD8 impairs clearance of herpes simplex virus from the nervous system: implications for the fate of virally infected neurons

J. Exp. Med.

Role of 4-1BB in immune responses

Semin. Immunol.

4-1BB: still in the midst of darkness

Mol. Cell

4-1BB promotes the survival of CD8⁺ T lymphocytes by increasing expression of Bcl-x_L and Bfl-1

J. Immunol.

4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T cells in a CD40-dependent manner

J. Immunol.

Cited by (36)

Non-identical twins: Different faces of CR3 and CR4 in myeloid and lymphoid cells of mice and men

CD11c<sup>+</sup>CD8<sup>+</sup> T cells: Two-faced adaptive immune regulators

Immune regulation and control of regulatory T cells by OX40 and 4-1BB

Combination of a MIP3α-antigen fusion therapeutic DNA vaccine with treatments of IFNα and 5-Aza-2’Deoxycytidine enhances activated effector CD8+ T cells expressing CD11c in the B16F10 melanoma model

Skin-Grafting and Dendritic Cell “Boosted” Humanized Mouse Models Allow the Pre-Clinical Evaluation of Therapeutic Cancer Vaccines

Decreased granzyme-B expression in CD11c<sup>+</sup>CD8<sup>+</sup> T cells associated with disease progression in patients with HBV-related hepatocellular carcinoma

4-1BB costimulation enhances HSV-1-specific CD8+ T cell responses by the induction of CD11c+CD8+ T cells

Abstract

Introduction

Section snippets

Mice, virus, and peptide

Characterization of 4-1BB-expressing CD4+ and CD8+ T cells after HSV-1 infection

Discussion

Acknowledgments

Virology

Cell Immunol.

Herpes simplex virus-specific CD8+ T cells can clear established lytic infections from skin and nerves and can partially limit the early spread of virus after cutaneous inoculation

J. Immunol.

Rapid cytotoxic T lymphocyte activation occurs in the draining lymph nodes after cutaneous herpes simplex virus infection as a result of early antigen presentation and not the presence of virus

J. Exp. Med.

Herpes simplex viruses

In Fundamental Immunology

Different roles for L3T4+ and Lyt 2+ T cell subsets in the control of an acute herpes simplex virus infection of the skin and nervous system

J. Gen. Virol.

Anti-CD8 impairs clearance of herpes simplex virus from the nervous system: implications for the fate of virally infected neurons

J. Exp. Med.

Role of 4-1BB in immune responses

Semin. Immunol.

4-1BB: still in the midst of darkness

Mol. Cell

4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1

J. Immunol.

4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T cells in a CD40-dependent manner

J. Immunol.

4-1BB costimulation enhances HSV-1-specific CD8⁺ T cell responses by the induction of CD11c⁺CD8⁺ T cells

Characterization of 4-1BB-expressing CD4⁺ and CD8⁺ T cells after HSV-1 infection

Herpes simplex virus-specific CD8⁺ T cells can clear established lytic infections from skin and nerves and can partially limit the early spread of virus after cutaneous inoculation

Different roles for L3T4⁺ and Lyt 2⁺ T cell subsets in the control of an acute herpes simplex virus infection of the skin and nervous system

4-1BB promotes the survival of CD8⁺ T lymphocytes by increasing expression of Bcl-x_L and Bfl-1