Dendritic Cell Regulation of T Helper Cells

Yin, Xiangyun; Chen, Shuting; Eisenbarth, Stephanie C.

doi:10.1146/annurev-immunol-101819-025146

Cited by 234 publications

(172 citation statements)

References 291 publications

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“…This model allows us to dissect the specific receptors and pathways required for the generation of detrimental alloimmunity during transfusion. Storing HOD RBCs for transfusion allows for examination of the innate and adaptive immune response to a model human RBC antigen after transfusion of RBCs stored under conditions that are used in hospitals globally (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)21). HOD RBCs processed and stored for 12 days at 4°C induced a robust anti-HOD alloantibody response post transfusion into wild type (WT) C57BL/6 mice.…”

Section: Resultsmentioning

confidence: 99%

“…In order to mount an adaptive immune response, specifically naïve T and B cell priming, first the innate immune system must be activated. This involves activation of antigen-presenting cells, such as dendritic cells (DCs), through innate immune receptors termed pattern recognition receptors (PRRs); this is a crucial checkpoint in regulating T cell-dependent B cell antibody responses (20). Indeed, our previous work demonstrated that although transfused RBCs are consumed by and activate numerous antigen presenting cells in the spleen, only type 2 conventional dendritic cells (cDC2s) were required for alloantibodies (21), likely due to a defect in T cell priming (22).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Innate and adaptive immunity to transfused allogenic red blood cells in mice requires MyD88

Soldatenko

Hoyt

et al. 2021

Preprint

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Red blood cell (RBC) transfusion therapy is essential for the survival of patients with hematological disorders such as sickle cell anemia. A potentially fatal complication of transfusion is development of non-ABO alloantibodies to polymorphic RBC antigens, yet mechanisms of alloantibody formation remain unclear. Human and mouse RBCs acquire a “storage lesion” prior to transfusion, which in mice contributes to immunogenicity. We previously reported that mouse splenic dendritic cells (DCs) are required for RBC alloimmunization and are activated by sterile and leukoreduced mouse RBCs after storage. Yet how syngeneic RBCs activate innate immune pathways to induce DC activation is unknown. We now show that DC activation to transfused RBCs occurs regardless of alloantigen presence, suggesting that RBC damage induced during storage triggers innate immune receptors. We discovered an unexpected dependence of RBC alloimmunization on the Toll-like receptor (TLR) signaling adaptor molecule MyD88. TLRs are a class of pattern recognition receptors (PRRs) that regulate DC activation and signal through two adaptor molecules, MyD88 and TRIF. We show that the inflammatory cytokine response, DC activation, and the subsequent alloantibody response to transfused syngeneic RBCs require MyD88 but not TRIF, suggesting a restricted set of PRRs are responsible for sensing RBCs and triggering alloimmunization.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Innate and adaptive immunity to transfused allogenic red blood cells in mice requires MyD88

Soldatenko

Hoyt

et al. 2021

Preprint

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“…CD4 T cell compartments can be broadly organized across three major classes of immune response. Divergent lineage defining protein and transcriptional signatures assort with type 1 inflammatory (targeting intracellular microbes), type 2 anti-inflammatory (targeting extracellular microbes), and type 3 mucosal (protecting barrier surfaces) immune response modules 24,25,26,27 .…”

Section: Highlightsmentioning

confidence: 99%

PD-1 checkpoint blockade activates germinal center follicular T cell programs that disrupt type 2 isotype-specific antibody homeostasis

Shuparski

Higgins

Miller

et al. 2021

Preprint

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Multiple CD4 T cell dependent tolerance mechanisms control adaptive B cell immunity to environmental antigens. We recently demonstrated a PD-1 checkpoint within steady-state splenic germinal centers (GC) that constrains the maturation of type 2 IgG1 isotype-specific antibody homeostasis. Here, we utilized single cell-indexed custom RNA-sequencing to probe the follicular T cell mechanisms directly targeted by acute PD-1 blockade. We find a pre-existing subset of follicular helper T (TFH) cells that express type 2 immune response properties (TFH2) with exaggerated pathways of TCR activation, cytokine signaling, and enhanced cell-cell contact upon acute PD-1 blockade. This selective amplification of the TFH2 program significantly increases predicted molecular connections to type 2 IgG1 GC B cells that dominate limited changes in GC localized follicular regulatory T (GC TFR) cell programs. These studies demonstrate how type 2 isotype-specific adaptive B cell tolerance is selectively disrupted by acute PD-1 blockade to reveal the modular regulatory mechanisms that control splenic GC dynamics at homeostasis.One Sentence SummaryAcute PD-1 blockade alters the regulatory dynamic of the steady state germinal center to drive the maturation of IgG1 GC B cells towards PC differentiation in a process mediated by type 2 like TFH effector molecules.HIGHLIGHTS-Acute PD-1 blockade enhances the steady state splenic TFH program-PD-1 blockade selectively exaggerates a Type 2 like TFH module-GC TFR cells are minimally impacted by blockade-PD-1 restrains predicted TFH2 functional contacts with IgG1 GC B Cells

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“…The microbe-tailored is the most prevalent and widely accepted model (Iwasaki and Medzhitov, 2015). It is an 'umbrella' term under which several sub-models are interchangeably used to explain how different pathogen-associated molecular patterns (PAMPs) activate various types of dendritic cells or other accessory cells to create different cytokine milieu that in turn drive different types of Th programs (Yin et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Pathological T Helper Polarization Requires Pre-existing Cross-Reactive Memory T Cells

Usharauli¹,

Kamala²

2021

Preprint

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Naive CD4+ T cells engage cognate peptide MHC-II complexes (pMHC-IIs) to differentiate and acquire one of several T helper (Th) fates whose specific trajectories are guided by a dynamic cytokine milieu that develops in response to antigenic entity. This physiological process is often erroneously conflated with a pathological one termed Th polarization. Using the SPIRAL model, we argue here that unlike Th fate choice, innate signaling alone is insufficient to initiate Th polarization in naive CD4+ T cells, that it instead develops from pre-existing memory CD4+ T cells that express cross-reactive TCRs, and that it inevitably leads to immunopathology.

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Dendritic Cell Regulation of T Helper Cells

Cited by 234 publications

References 291 publications

Innate and adaptive immunity to transfused allogenic red blood cells in mice requires MyD88

Innate and adaptive immunity to transfused allogenic red blood cells in mice requires MyD88

PD-1 checkpoint blockade activates germinal center follicular T cell programs that disrupt type 2 isotype-specific antibody homeostasis

Pathological T Helper Polarization Requires Pre-existing Cross-Reactive Memory T Cells

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