The Roles of CD28 and CD40 Ligand in T Cell Activation and Tolerance

Howland, Kimberly C.; Ausubel, Lara J.; London, Cheryl A.; Abbas, Abul K.

doi:10.4049/jimmunol.164.9.4465

Cited by 162 publications

(127 citation statements)

References 28 publications

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“…The addition of canarypox expressing CD40L had not only increased specific CD8 + T cell responses qualitatively but also improved the quality of CD8 + T cells as exhibited by more specific polyfunctional CD8 + T cells and potentially more long lived memory CD8 + T cells as determined by IL-7Rα staining. Some previous reports suggested that CD40L is also important for enhancing CD4 + T cell responses [56][57][58]. Our data are consistent with these reports in that the CD40L regimens enhanced splenocyte proliferation and Th1 cytokine production to vaccine antigens, however, only when CD40L was expressed as a membrane molecule in canarypox vector.…”

Section: Discussionsupporting

confidence: 92%

CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals

Liu

Stone

et al. 2008

Vaccine

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SummaryHuman immunodeficiency virus-1 (HIV-1) canarypox vaccines are safe but poorly immunogenic. CD40 ligand (CD40L), a member of the tumor necrosis factor superfamily (TNFSF), is a pivotal co-stimulatory molecule for immune responses. To explore whether CD40L can be used as an adjuvant for HIV-1 canarypox vaccine, we constructed recombinant canarypox viruses expressing CD40L. Co-immunization of mice with CD40L expressing canarypox and the canarypox vaccine expressing HIV-1 proteins, vCP1452, augmented HIV-1 specific cytotoxic T lymphocyte (CTL) responses in terms of frequency, polyfunctionality and interleukin (IL)-7 receptor α chain (IL-7Rα, CD127) expression. In addition, CD40L expressed from canarypox virus could significantly augment CD4 + T cell responses against HIV-1 in mice. CD40L expressed from canarypox virus matured human monocyte-derived dendritic cells (MDDCs) in a tumor necrosis factor α (TNF-α) independent manner, which underwent less apoptosis, and could expand ex vivo Epstein-Barr virus (EBV)-specific CTL responses from healthy human individuals and ex vivo HIV-1-specific CTL responses from HIV-1-infected individuals in the presence or absence of CD4 + T cells. Taken together, our results suggest that CD40L incorporation into poxvirus vectors could be used as a strategy to enhance their immunogenicity.

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Section: Discussionsupporting

confidence: 92%

CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals

Liu

Stone

et al. 2008

Vaccine

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“…non-pathogenic) response in CD154 -/-mice. A recent report has shown that CD154 -/-TCR-transgenic T cells can initially expand, but cannot sustain a Th1 response [24]. We show here that CD154 -/-mice mount a strong Th2 response under conditions that promote a Th1 response in CD154-sufficient mice (CFA normally drives a Th1 response in most experimental systems [25]).…”

Section: Resultsmentioning

confidence: 55%

“…The CD40-CD154 interaction in tolerance induction is controversial with previous studies suggesting that CD154 either was, or was not required [24,27]. To investigate this in our system, we switched from using pMOG to the OVA(323-339) peptide (pOVA), because in later experiments we used OT-II transgenic T cells [22], expressing a TCR that reacts with this peptide in association with I-A b .…”

Section: Cd40-cd154 Signalling Is Not Required For the Induction Of Tmentioning

confidence: 99%

Circumventing tolerance at the T cell or the antigen‐presenting cell surface: Antibodies that ligate CD40 and OX40 have different effects

2006

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An adjuvant can be defined as an agent that non‐specifically promotes the immune response to an accompanying antigen. Ligation of CD40 on the surface of the antigen‐presenting cell leads to upregulation of OX40 ligand which, in turn, ligates OX40 on the activated T cell resulting in prolonged T cell proliferation/survival, boosting the immune response. Thus agonistic anti‐CD40 and anti‐OX40 might be viewed as “adjuvant antibodies” and have been shown in diverse experimental systems to either boost immune responses or prevent the establishment of immunological tolerance. Here we describe that both these antibodies are able to prevent the induction of tolerance induced using soluble peptide antigen. However, unlike lipopolysaccharide, they are not sufficient to convert tolerance to immunity (i.e. they are not true adjuvants in this system). Using mice that are prone to either Th1 or Th2 immunity under identical immunization conditions, we show that the effects of anti‐OX40 are quantitative – boosting whichever response is dominant. In contrast, anti‐CD40 boosts Th1 immunity and converts a Th2 response to Th1. We conclude that, although these two antibodies seem to impact on the same molecular pathway of costimulation to prevent tolerance, their effects are qualitatively distinct and their use cannot be viewed as interchangeable.

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“…Previous studies have demonstrated that CD28 costimulation is required for initiating and sustaining T-cell clonal expansion and differentiation in response to antigen recognition (21)(22)(23)(24)(25). Furthermore, CD28-B7 costimulatory blockade has been shown to inhibit clonal expansion (26) and effector cell differentiation in vivo (27).…”

Section: Effect Of Cd28-b7 Costimulatory Blockade On Alloantigen-specmentioning

confidence: 99%

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

Sandner

Salama

Houser

et al. 2003

American Journal of Transplantation

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We have developed an adoptive transfer model system to visualize the dynamics of alloantigen-specific CD4 + T-cell activation in vivo. Using TCR-transgenic (tg) mice reactive to I-A bm12 , we studied the clonal expansion and differentiation of alloreactive T cells by tracking the fate of adoptively transferred TCR-tg CD4 + T cells in syngeneic mice transplanted with skin grafts expressing I-A bm12 . Following transplantation, alloantigen-specific TCR-tg CD4 + T-cell expansion was observed initially in the draining lymph nodes followed by the spleen. TCR-tg CD4 + T cells up-regulated CD69 and CD25 expression, developed an effector/memory surface phenotype and produced IFN-c in response to alloantigen ex vivo. Furthermore, we validate the model system as a means for studying the effects of tolerogenic regimens on alloreactive CD4 + T cells, demonstrating that CTLA4Ig inhibits alloantigen-dependent clonal expansion and effector function of TCR-tg CD4 + T cells in vivo. We describe the first model for tracking alloreactive CD4 + T-cell activation in vivo. It provides a powerful tool for studying CD4 + T-cell mediated alloimmune responses and mechanisms of tolerance induction in vivo.

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The Roles of CD28 and CD40 Ligand in T Cell Activation and Tolerance

Cited by 162 publications

References 28 publications

CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals

CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals

Circumventing tolerance at the T cell or the antigen‐presenting cell surface: Antibodies that ligate CD40 and OX40 have different effects

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

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