Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10–producing suppressive CD4+ T cells

Li, Dapeng; Romain, Gabrielle; Flamar, Anne-Laure; Duluc, Dorothée; Dullaers, Mélissa; Li, Xiao Hua; Zurawski, Sandra; Bosquet, Nathalie; Palucka, A. Karolina; Grand, Roger Le; O’Garra, Anne; Banchereau, Jacques; Oh, Sang Kon

doi:10.1084/jem.20110399

Cited by 157 publications

(206 citation statements)

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“…In the steady state, this signaling leads to the induction of tolerance and can be considered a major anti-inflammatory pathway. This mechanism has been exploited to induce IL-10-producing suppressive CD4 + T cells targeting self and foreign antigens to DCs via the DC-asialoglycoprotein receptor [13]. The induction of such suppressive T cells requires p38/extracellular signal-regulated kinase phosphorylation and IL-10 induction in DCs.…”

Section: The Scavenger Receptors: a Multifunctional And Structurally mentioning

confidence: 99%

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

et al. 2017

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Scavenger receptors (SRs) are structurally heterogeneous cell surface receptors characterized by their capacity to remove extraneous or modified self-macromolecules from circulation, thus avoiding the accumulation of noxious agents in the extracellular space. This scavenging activity makes SRs important molecules for host defense and homeostasis. In turn, SRs keep the activation of the steady-state immune response in check, and participate as co-receptors in the priming of the effector immune responses when the macromolecules are associated with a threat that might compromise host homeostasis. Therefore, SRs built up sophisticated sensor mechanisms controlling the immune system, which may be exploited to develop novel drugs for cancer immunotherapy. In this review, we focus on the regulation of the anti-tumor immune response by two paradigmatic SRs: the lymphocyte receptor CD5 and the more broadly distributed scavenger receptor class B type 1 (SR-B1). Cancer immunity can be boosted by blockade of SRs working as immune checkpoint inhibitors (CD5) and/or by proper engagement of SRs working as innate danger receptor (SR-B1). Thus, these receptors illustrate both the complexity of targeting SRs in cancer immunotherapy and also the opportunities offered by such an approach. Keywords:Cancer immunotherapy r CD5 r Danger signal r Immune-checkpoint r Scavenger receptor r Scavenger receptor class B type 1 r Toll-like receptors IntroductionThe cancer-immunity cycle can be subverted by tumors at many steps, thus novel therapeutic interventions should be considered for all these possibilities [1]. This cycle starts with the release of tumor antigens and their subsequent capture by professional antigen-presenting cells (mainly, dendritic cells; DCs) for the activation of effector cells of the innate and adaptive immune Correspondence: Dr. Pedro Berraondo e-mail: pberraondol@unav.es system. This is a highly regulated process aimed at maintaining the integrity of the host without inducing significant side effects (e.g., inflammation or autoimmunity) [2]. Tissue homeostasis involves phagocytic processes to remove the excess of native or modified molecules from unviable or stressed cells, as well as from invading microbial agents [3]. Such molecules include lipids, whose intracellular levels should be carefully controlled to sustain proper cell metabolism; endogenous glyco-and lipo-proteins, damaged or * These authors contributed equally to this work. * * These authors are senior co-authors of this work. [4,5]. This phagocytic activity should be coupled to an alarm signal system that awakens other effector mechanisms of the immune system when the tissue damage cannot be controlled by the removal of the endogenous or exogenous molecules. To this end, the immune system has a myriad of specialized soluble or membrane-bound receptors called pattern recognition receptors (PRRs). These PRRs are non-polymorphic, nonclonally distributed, and germ-line encoded receptors recognizing microorganism-associated molecular patterns (MAMPs) -tha...

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Section: The Scavenger Receptors: a Multifunctional And Structurally mentioning

confidence: 99%

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

et al. 2017

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“…The CD4 + T-cell subsets, Th1 and Th2 (10), were the first to be characterized. Subsequently, other subsets have been identified and include Tregs, Th17, Tfh, and Th9 (11). CD8 + T-cell subsets have also been divided into subsets based on their cytokine production profile (12)(13)(14).…”

Section: Endritic Cells (Dcs) Are Potent Antigen-presenting Cells (mentioning

confidence: 99%

Immunoglobulin-like transcript receptors on human dermal CD14⁺dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming

Banchereau

Zurawski

Thompson-Snipes

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Human Langerhans cells (LCs) are highly efficient at priming cytolytic CD8 + T cells compared with dermal CD14 + dendritic cells (DCs). Here we show that dermal CD14 + DCs instead prime a fraction of naïve CD8 + T cells into cells sharing the properties of type 2 cytokinesecreting CD8 + T cells (TC2). Differential expression of the CD8-antagonist receptors on dermal CD14 + DCs, the Ig-like transcript (ILT) inhibitory receptors, explains the difference between the two types of DCs. Inhibition of CD8 function on LCs inhibited cytotoxic T lymphocytes (CTLs) and enhanced TC2 generation. In addition, blocking ILT2 or ILT4 on dermal CD14 + DCs enhanced the generation of CTLs and inhibited TC2 cytokine production. Lastly, addition of soluble ILT2 and ILT4 receptors inhibited CTL priming by LCs. Thus, ILT receptor expression explains the polarization of CD8 + T-cell responses by LCs vs. dermal CD14 + DCs.D endritic cells (DCs) are potent antigen-presenting cells (APCs) responsible for inducing Ag-specific immunity and tolerance (1). Several populations of DCs take up residence in different tissues and carry common as well as unique biological functions (2, 3). The healthy human skin displays at least three DC populationsLangerhans cells (LCs) in the epidermis and interstitial CD1a + and CD14 + DCs in the dermis (4, 5). Each of the different skin DC subsets carries out specialized functions. CD14 + DCs that reside in the dermis are particularly efficient at controlling the differentiation of naïve B cells into plasma cells (6, 7). Epidermal LCs, conversely, are highly efficient at priming naïve CD8 + T cells into potent cytotoxic T lymphocytes (CTLs). Both DC subsets are equally efficient at inducing a secondary CD8 + T-cell response (7-9).T lymphocytes are also composed of subsets. The CD4 + T-cell subsets, Th1 and Th2 (10), were the first to be characterized. Subsequently, other subsets have been identified and include Tregs, Th17, Tfh, and Th9 (11). CD8 + T-cell subsets have also been divided into subsets based on their cytokine production profile (12)(13)(14). Type 1 cytokine-producing T cells (TC1) express IFN-γ and TNF-α, whereas type 2 cytokine-producing T cells (TC2) produce IL-4, -5, and -13. Suppressor CD8 + T cells produce IL-10 and TGF-β and are characterized by low expression levels of CD8 and CD28 (15,16). These findings are physiologically relevant because the balance between TC1 to TC2 and CD8 + suppressor T cell populations correlates with a patient's ability to overcome tumor overgrowth or viral infections.Studies with CD8-α or CD8-β gene-targeted mice have revealed that CD8 plays a key role in the maturation and function of MHC class I-restricted T lymphocytes (17,18). Interacting with MHC in the immunological synapse, a specialized junction between a T lymphocyte and an APC, CD8 can enhance the affinity of T-cell receptor (TCR)-CD8 complexes for MHC-peptide (pMHC) complexes by ∼10-fold (19). The importance of CD8 is also demonstrated by the function of two inhibitory receptors, ILT2 and ILT4, that can...

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“…Env gp140 sequence derived from the codon-optimized HIV-1 96ZM651 synthetic construct (NIH AIDS reagent program, GenBank accession number AY181197.1 residues 94 to 2064) was inserted at the IgG4 heavy-chain C-terminal codon distal to a flexV1 flexible linker spacer (9) and proximal to 6 His codons. Anti-LOX-1.Env gp140 (2) was derived from the parental anti-human LOX-1 15C4 recombinant human IgG4 MAb (3,22) (GenBank accession numbers KM246787 and KM246788) via humanization of the mouse variable regions (Antitope, Ltd.). This was fused to Env gp140 sequence as described above.…”

Section: Methodsmentioning

confidence: 99%

Superiority in Rhesus Macaques of Targeting HIV-1 Env gp140 to CD40 versus LOX-1 in Combination with Replication-Competent NYVAC-KC for Induction of Env-Specific Antibody and T Cell Responses

Zurawski

Shen

Zurawski

et al. 2017

J Virol

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We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic cells (DCs), in rhesus macaques primed with a poxvirus vector (NYVAC-KC) expressing Env gp140. The DC-targeting vaccines, humanized recombinant monoclonal antibodies fused to Env gp140, were administered as a boost with poly-ICLC adjuvant either alone or coadministered with the NYVAC-KC vector. All the DC-targeting vaccine administrations with poly-ICLC increased the low-level serum anti-Env IgG responses elicited by NYVAC-KC priming significantly more (up to a P value of 0.01) than in a group without poly-ICLC. The responses were robust and cross-reactive and contained antibodies specific to multiple epitopes within gp140, including the C1, C2, V1, V2, and V3, C4, C5, and gp41 immunodominant regions. The DC-targeting vaccines also elicited modest serum Env-specific IgA responses. All groups gave serum neutralization activity limited to tier 1 viruses and antibodydependent cytotoxicity responses (ADCC) after DC-targeting boosts. Furthermore, CD4 ϩ and CD8 ϩ T cell responses specific to multiple Env epitopes were strongly boosted by the DC-targeting vaccines plus poly-ICLC. Together, these results indicate that prime-boost immunization via NYVAC-KC and either anti-CD40.Env gp140/poly-ICLC or anti-LOX-1.Env gp140/poly-ICLC induced balanced antibody and T cell responses against HIV-1 Env. Coadministration of NYVAC-KC with the DC-targeting vaccines increased T cell responses but had minimal effects on antibody responses except for suppressing serum IgA responses. Overall, targeting Env to CD40 gave more robust T cell and serum antibody responses with broader epitope representation and greater durability than with LOX-1.

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Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10–producing suppressive CD4+ T cells

Abstract: Targeting antigens to the lectinlike DC-ASGPR receptor on human DCs and in nonhuman primates results in the induction of antigen-specific IL-10–producing CD4+ T cells.

Cited by 157 publications

References 53 publications

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

Immunoglobulin-like transcript receptors on human dermal CD14⁺dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming

Superiority in Rhesus Macaques of Targeting HIV-1 Env gp140 to CD40 versus LOX-1 in Combination with Replication-Competent NYVAC-KC for Induction of Env-Specific Antibody and T Cell Responses

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Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10–producing suppressive CD4+ T cells

Abstract: Targeting antigens to the lectinlike DC-ASGPR receptor on human DCs and in nonhuman primates results in the induction of antigen-specific IL-10–producing CD4+ T cells.

Cited by 157 publications

References 53 publications

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

Immunoglobulin-like transcript receptors on human dermal CD14+dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming

Superiority in Rhesus Macaques of Targeting HIV-1 Env gp140 to CD40 versus LOX-1 in Combination with Replication-Competent NYVAC-KC for Induction of Env-Specific Antibody and T Cell Responses

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Immunoglobulin-like transcript receptors on human dermal CD14⁺dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming