Lack of Intrinsic CTLA-4 Expression Has Minimal Effect on Regulation of Antiviral T-Cell Immunity

Homann, Dirk; Dummer, Wolfgang; Wolfe, Tom; Rodrigo, Evelyn; Theofilopoulos, Argyrios N.; Oldstone, Michael B. A.; Herrath, Matthias G. von

doi:10.1128/jvi.80.1.270-280.2006

Cited by 50 publications

(44 citation statements)

References 94 publications

(106 reference statements)

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“…Our data suggest that effector T cells contribute to non-cell autonomous inhibition of immune responses by CTLA-4 commonly attributed to Tregs (14,19,(26)(27)(28). Our results, and results described in a companion paper (29), provide functional evidence for a model in which CTLA-4 expressed on activated effector T cells and Tregs inhibits T cell responses in similar ways (4,6).…”

Section: Ctla-4 Expressed On Effector T Cells Inhibits T Cell Responssupporting

confidence: 64%

Cutting Edge: CTLA-4 on Effector T Cells Inhibits In Trans

Corse

Allison

2012

The Journal of Immunology

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CTLA-4 is thought to inhibit effector T cells both intrinsically, by competing with CD28 for B7 ligands, and extrinsically, through the action of regulatory T cells (Tregs). We studied in vivo responses of normal and CTLA-4–deficient Ag-specific murine effector CD4+ T cells. We directly demonstrate that effector T cell-restricted CTLA-4 inhibits T cell responses in a cell-extrinsic manner. Cotransfer experiments show that CTLA-4 on normal effector CD4+ T cells completely abrogates the dramatically increased expansion normally experienced by their CTLA-4–deficient counterparts. Neither the wild-type nor the CTLA-4–deficient T cells express the Treg transcription factor Foxp3 when transferred alone or together. Thus, cell-extrinsic inhibition of T cell responses by CTLA-4 is not limited to Tregs but is also a function of effector T cells.

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Section: Ctla-4 Expressed On Effector T Cells Inhibits T Cell Responssupporting

confidence: 64%

Cutting Edge: CTLA-4 on Effector T Cells Inhibits In Trans

Corse

Allison

2012

The Journal of Immunology

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“…The notion of inhibitory rather than stimulatory CD80/86 activities has also been extended to "reverse signaling," indoleamine 2,3-dioxygenase (IDO) induction, T REG s, and their reliance on CD80/86 interactions (52,64). While our previous work has documented that IDO contributes to only a modest inhibition of primary LCMV-specific CD4 ϩ but not CD8 ϩ T E responses (35), no reports that document the inhibition of LCMV-specific CD8 ϩ T E immunity by T REG s have been published to date. The observation that T REG depletion can in fact enhance primary and, in particular, secondary LCMV-specific CD8 ϩ T E responses ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…All monoclonal antibodies were purchased as fluorophore-conjugated reagents from ebioscience, Biolegend, BDBiosciences, or RnD Systems; chemokinespecific polyclonal goat antibodies were obtained from RnD Systems. D b NP 396-404 , D b GP [33][34][35][36][37][38][39][40][41] , and I-A b GP [66][67][68][69][70][71][72][73][74][75][76][77] MHC-peptide complexes were provided as biotinylated monomers and/or fluorophore-conjugated tetramers by the NIH tetramer core facility and used for the flow cytometrybased identification of LCMV-specific CD8 ϩ and CD4 ϩ T cells as described previously (39); essentially the same results were obtained by using I-A b GP [66][67][68][69][70][71][72][73][74][75][76][77] and I-A b GP 61-80 tetramers generated in the laboratory (not shown). The methodologies for cell surface (antibodies and MHC tetramers) and intracellular staining, including the detection of cytokines, members of the tumor necrosis factor superfamily (TNFSFs), CTLA-4, chemokines, and bromodeoxyuridine (BrdU), were detailed elsewhere previously (19,35,39,49).…”

Section: Micementioning

confidence: 99%

Multiple Layers of CD80/86-Dependent Costimulatory Activity Regulate Primary, Memory, and Secondary Lymphocytic Choriomeningitis Virus-Specific T Cell Immunity

Eberlein

Davenport

Nguyen

et al. 2012

J Virol

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The lymphocytic choriomeningitis virus (LCMV) system constitutes one of the most widely used models for the study of infectious disease and the regulation of virus-specific T cell immunity. However, with respect to the activity of costimulatory and associated regulatory pathways, LCMV-specific T cell responses have long been regarded as relatively independent and thus distinct from the regulation of T cell immunity directed against many other viral pathogens. Here, we have reevaluated the contribution of CD28-CD80/86 costimulation in the LCMV system by use of CD80/86-deficient mice, and our results demonstrate that a disruption of CD28-CD80/86 signaling compromises the magnitude, phenotype, and/or functionality of LCMVspecific CD8 ؉ and/or CD4 ؉ T cell populations in all stages of the T cell response. Notably, a profound inhibition of secondary T cell immunity in LCMV-immune CD80/86-deficient mice emerged as a composite of both defective memory T cell development and a specific requirement for CD80 but not CD86 in the recall response, while a related experimental scenario of CD28-dependent yet CD80/86-independent secondary CD8 ؉ T cell immunity suggests the existence of a CD28 ligand other than CD80/ 86. Furthermore, we provide evidence that regulatory T cells (T REG s), the homeostasis of which is altered in CD80/86 ؊/؊ mice, contribute to restrained LCMV-specific CD8 ؉ T cell responses in the presence of CD80/86. Our observations can therefore provide a more coherent perspective on CD28-CD80/86 costimulation in antiviral T cell immunity that positions the LCMV system within a shared context of multiple defects that virus-specific T cells acquire in the absence of CD28-CD80/86 costimulation.T he generation of specific T cell immunity is governed by multiple determinants that shape the proliferative expansion and functional maturation of effector T cells (T E ) as well as their subsequent differentiation into memory T cells (T M ). Conceptualization of these processes permits the straightforward demarcation of T cell receptor (TCR)-peptide/major histocompatibility complex (MHC) interactions ("signal 1"), yet the simple notion of a defined "costimulus" required for the optimization of specific T cell responses, historically referred to as "signal 2," has been eroded by the realization that a multiplicity of diverse receptor-ligand interactions between T cells and antigen-presenting cells (APCs), soluble factors (e.g., cytokines), and specific temporospatial constraints operate in concert to control the eventual magnitude as well as the molecular, phenotypic, and functional properties of responding T E populations. Thus, it is the integration of signals derived from a large complex of stimulatory and inhibitory interactions that permits activated T cells the translation of minimal kinetic alterations into profound modifications of the ensuing T cell response (26,84). Insofar as these interactions produce a kinetic, quantitative, and/or qualitative enhancement of specific T cell immunity, individual components with...

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“…Specifically, expansion but not differentiation is regulated by CD152, which leads to an overall reduction in cytokine secretion due to reduced numbers of effector cells, but not due to reduced cytokine secretion of individual cells (22). In addition, it has been shown that CD152 signaling on CD8 T lymphocytes has no significant function in vivo (25,26). Therefore, regarding primary CD8 T lymphocyte responses, the precise function of CD152 is largely undefined.…”

Section: D8mentioning

confidence: 99%

High IFN-γ Production of Individual CD8 T Lymphocytes Is Controlled by CD152 (CTLA-4)

Pandiyan

Hegel

Krueger

et al. 2007

The Journal of Immunology

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CD8 T cell expansion and cytokine production is needed to generate an effective defense against viral invasion of the host. These features of CD8 T lymphocytes are regulated, especially during primary responses, by positive and negative costimulation. We show in this study that surface expression of CD152 is highly up-regulated on activated CD8 T lymphocytes during primary immune responses, suggesting a prominent regulatory role. Indeed, production of the proinflammatory cytokine IFN-γ, but not TNF-α, by CD8 T cells was inhibited by CD152 engagement. The inhibition was regulated independent of proliferation and IL-2 production, but dependent on the quality of the TCR signaling. We show that signals induced by CD152 on activated CD8 T lymphocytes reduce the frequency of IFN-γhigh-expressing cells. Our data also show that in activated CD8 T cells, the CD152-mediated inhibition of cytokine production is more pronounced than inhibition of their proliferation.

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Lack of Intrinsic CTLA-4 Expression Has Minimal Effect on Regulation of Antiviral T-Cell Immunity

Cited by 50 publications

References 94 publications

Cutting Edge: CTLA-4 on Effector T Cells Inhibits In Trans

Cutting Edge: CTLA-4 on Effector T Cells Inhibits In Trans

Multiple Layers of CD80/86-Dependent Costimulatory Activity Regulate Primary, Memory, and Secondary Lymphocytic Choriomeningitis Virus-Specific T Cell Immunity

High IFN-γ Production of Individual CD8 T Lymphocytes Is Controlled by CD152 (CTLA-4)

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