Dataset Information

CD4/CD8/Dendritic cell complexes in the spleen: CD8+ T cells can directly bind CD4+ T cells and modulate their response.

ABSTRACT: CD4+ T cell help to CD8+ T cell responses requires that CD4+ and CD8+ T cells interact with the same antigen presenting dendritic cell (Ag+DC), but it remains controversial whether helper signals are delivered indirectly through a licensed DC and/or involve direct CD4+/CD8+ T cell contacts and/or the formation of ternary complexes. We here describe the first in vivo imaging of the intact spleen, aiming to evaluate the first interactions between antigen-specific CD4+, CD8+ T cells and Ag+DCs. We show that in contrast to CD4+ T cells which form transient contacts with Ag+DC, CD8+ T cells form immediate stable contacts and activate the Ag+DC, acquire fragments of the DC membranes by trogocytosis, leading to their acquisition of some of the DC properties. They express MHC class II, and become able to present the specific Marilyn peptide to naïve Marilyn CD4+ T cells, inducing their extensive division. In vivo, these CD8+ T cells form direct stable contacts with motile naïve CD4+ T cells, recruiting them to Ag+DC binding and to the formation of ternary complexes, where CD4+ and CD8+ T cells interact with the DC and with one another. The presence of CD8+ T cells during in vivo immune responses leads to the early activation and up-regulation of multiple functions by CD4+ T lymphocytes. Thus, while CD4+ T cell help is important to CD8+ T cell responses, CD8+ T cells can interact directly with naïve CD4+ T cells impacting their recruitment and differentiation.

SUBMITTER: Barinov A

PROVIDER: S-EPMC5501581 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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CD4/CD8/Dendritic cell complexes in the spleen: CD8+ T cells can directly bind CD4+ T cells and modulate their response.

Barinov Aleksandr A Galgano Alessia A Krenn Gerald G Tanchot Corinne C Vasseur Florence F Rocha Benedita B

PloS one 20170707 7

CD4+ T cell help to CD8+ T cell responses requires that CD4+ and CD8+ T cells interact with the same antigen presenting dendritic cell (Ag+DC), but it remains controversial whether helper signals are delivered indirectly through a licensed DC and/or involve direct CD4+/CD8+ T cell contacts and/or the formation of ternary complexes. We here describe the first in vivo imaging of the intact spleen, aiming to evaluate the first interactions between antigen-specific CD4+, CD8+ T cells and Ag+DCs. We ...[more]

PMID: 28686740

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Project description:Dendritic cells (DCs) are antigen-presenting cells essential for the induction of adaptive immune responses. Their unprecedented ability to present antigens to T cells has made them excellent targets for vaccine development. In the last years, a new technology based on antigen delivery directly to different DC subsets through the use of hybrid monoclonal antibodies (mAbs) to DC surface receptors fused to antigens of interest opened new perspectives for the induction of robust immune responses. Normally, the hybrid mAbs are administered with adjuvants that induce DC maturation. In this work, we targeted an antigen to the CD8?+ or the CD8?- DC subsets in the presence of CpG oligodeoxinucleotides (ODN) or bacterial flagellin, using hybrid ?DEC205 or ?DCIR2 mAbs, respectively. We also accessed the role of toll-like receptors (TLRs) 5 and 9 signaling in the induction of specific humoral and cellular immune responses. Wild-type and TLR5 or TLR9 knockout mice were immunized with two doses of the hybrid ?DEC205 or ?DCIR2 mAbs, as well as with an isotype control, together with CpG ODN 1826 or flagellin. A chimeric antigen containing the Plasmodium vivax 19?kDa portion of the merozoite surface protein (MSP119) linked to the Pan-allelic DR epitope was fused to each mAb. Specific CD4+ T cell proliferation, cytokine, and antibody production were analyzed. We found that CpG ODN 1826 or flagellin were able to induce CD4+ T cell proliferation, CD4+ T cells producing pro-inflammatory cytokines, and specific antibodies when the antigen was targeted to the CD8?+ DC subset. On the other hand, antigen targeting to CD8?- DC subset promoted specific antibody responses and proliferation, but no detectable pro-inflammatory CD4+ T cell responses. Also, specific antibody responses after antigen targeting to CD8?+ or CD8?- DCs were reduced in the absence of TLR9 or TLR5 signaling, while CD4+ T cell proliferation was mainly affected after antigen targeting to CD8?+ DCs and in the absence of TLR9 signaling. These results extend our understanding of the modulation of specific immune responses induced by antigen targeting to DCs in the presence of different adjuvants. Such knowledge may be useful for the optimization of DC-based vaccines.

Project description:BackgroundStudies assessing immune parameters typically utilize human PBMCs or murine splenocytes to generate data that is interpreted as representative of immune status. Using splenocytes, we have shown memory CD4-T cells that expand following systemic immunostimulatory therapies undergo rapid IFNg-mediated activation induced cell death (AICD) resulting in a net loss of total CD4-T cells which correlates with elevated PD-1 expression. This is in contrast to CD8-T cells which expand with minimal PD-1 upregulation and apoptosis. In this study we expand upon our previous work by evaluating CD4 and CD8-T cell phenotype and distribution in peripheral organs which are more representative of immune responses occurring at metastatic sites following immunotherapy.MethodsPhenotypic assessment of T cells in both lymphoid (spleen and LN) as well as peripheral organs (liver and lungs) in control and immunotherapy treated mice was performed to survey the impact of location on memory phenotype and activation marker status. Peripheral blood from patients undergoing systemic high dose IL-2 was also assessed for expression of PD-1 and memory phenotype.ResultsHere we reveal that, similar to what occurs in the spleen and lymph nodes, CD4-T cell numbers decreased while CD8-T cells expanded at these peripheral sites. In contrast to having differential expression of PD-1 as occurs in the spleen, both CD4 and CD8-T cells had significantly elevated levels of PD-1 in both the liver and lungs. Further analysis correlated PD-1 expression to CD62Llow (T effector/effector memory,TE/EM) expression which are more prevalent in CD4-T cells in general as well as CD8-T cells in peripheral organs. Similar elevated PD-1 expression on TE/EM cells was observed in patients undergoing systemic high-dose IL-2 therapy.ConclusionsThese data highlight PD-1 expressing and/or TE/EM subsets of T cells in circulation as more representative of cells at immune sites and underscore the importance of valuation both in lymphoid as well as target organs when making determinations about immune status.Trial registrationClinicalTrials.gov NCT01416831. Registered August 12, 2011.

Dataset Information

CD4/CD8/Dendritic cell complexes in the spleen: CD8+ T cells can directly bind CD4+ T cells and modulate their response.

Publications

CD4/CD8/Dendritic cell complexes in the spleen: CD8+ T cells can directly bind CD4+ T cells and modulate their response.

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