Interleukin-2-Dependent Allergen-Specific Tissue-Resident Memory Cells Drive Asthma

Hondowicz, Brian D.; An, Dowon; Schenkel, Jason M.; Kim, Karen S.; Steach, Holly R.; Krishnamurty, Akshay T.; Keitany, Gladys J.; Garza, Esteban N.; Fraser, Kathryn; Moon, James; Altemeier, William A.; Masopust, David; Pepper, Marion

doi:10.1016/j.immuni.2015.11.004

Cited by 231 publications

(254 citation statements)

References 60 publications

(80 reference statements)

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“…6a–e). Thus, while we see the overall same reduction in T H 2 as Ballesteros-Tato et al , it is equally plausible that low ICOS on the T resident memory cells (T RM ) would mean that both T FH and T RM models (41) could be operable here. The increased T H 1 and T H 17 responses seen in an active EAE model (Fig.…”

Section: Discussionsupporting

confidence: 79%

ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses

Lownik

Luker

Damle

et al. 2017

The Journal of Immunology

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The proper regulation of inducible costimulator (ICOS) and its ligand (ICOSL) have been shown to be essential for maintaining proper immune homeostasis. Loss of either protein results in defective humoral immunity, and overexpression of ICOS results in aberrant antibody production resembling lupus. How ICOSL is regulated in response to ICOS interaction is still unclear. We demonstrate that ADAM10 is the primary physiological sheddase of ICOSL in both mouse and human. Using an in vivo system in which ADAM10 is deleted only on B cells (ADAM10B−/−), elevated levels of ICOSL were seen. This increase is also seen when ADAM10 is deleted from human B cell lines. Identification of the primary sheddase has allowed the characterization of a novel mechanism of ICOS regulation. In wildtype (WT) mice, interaction of ICOSL/ICOS results in ADAM10 induced shedding of ICOSL on B cells and moderate ICOS internalization on T cells. When this shedding is blocked, excessive ICOS internalization occurs. This results in severe defects in T follicular helper (TFH) development and TH2 polarization, seen in a house dust mite exposure model. In addition, enhanced TH1 and TH17 immune responses are seen in experimental allergic encephalomyelitis. Blockade of ICOSL rescues T cell ICOS surface expression and at least partially rescues both TFH numbers and the abnormal antibody production previously reported in these mice. Overall, we propose a novel regulation of the ICOS/ICOSL axis, with ADAM10 playing a direct role in regulating ICOSL as well as indirectly regulating ICOS, thus controlling ICOS/ICOSL-dependent responses.

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Section: Discussionsupporting

confidence: 79%

ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses

Lownik

Luker

Damle

et al. 2017

The Journal of Immunology

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“…Resting memory CD4 T cells appear to be largely stable over time by major lineage-defining phenotypic markers, as shown for antigen-specific T FH , T H 1, and T H 2 cells in mouse models (Harrington et al 2008;Hale et al 2013;Hondowicz et al 2016;Tubo et al 2016). Human data support the same conclusion but the antigen-specific data are limited (Locci et al 2013;Bancroft et al 2016;Da Silva Antunes et al 2017).…”

Section: Memory Cd4 T-cell Phenotype Heterogeneity and Stability Durimentioning

confidence: 66%

Do Memory CD4 T Cells Keep Their Cell-Type Programming: Plasticity versus Fate Commitment?

Crotty

2017

Cold Spring Harb Perspect Biol

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Plasticity is the ability of a cell type to convert to another cell type. There are multiple effector CD4 T-cell subtypes, including T1, T2, T17, T1*, CD4 CTL, T9, and T cells. It is commonly thought that a CD4 T cell can readily show full plasticity-full conversion from one differentiated cell-and this propensity to plasticity is possessed by memory CD4 T cells. However, there remains no direct demonstration of in vivo-generated resting memory CD4 T-cell conversion to a different subtype on secondary antigen challenge in vivo in an intact animal at the single-cell level. What has been clearly shown is that CD4 T cells possess extraordinary capacity for phenotypic heterogeneity, but that is a distinct property from plasticity. Heterogeneity is diversity of the resting memory CD4 T-cell population, not conversion of a single differentiated cell into another subtype. Apparently, plasticity at the population level can be accomplished by either mechanism, as heterogeneity of CD4 T-cell subpopulations could affect large shifts in subtype distribution at the overall population level via differential exponential expansion and death.

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“…In a dust mite model such lung-resident memory cells are sufficient to induce AHR in situ and persist for up to 100 days. 35 In other work, IL-4 receptor (IL-4R) α–responsive T H 2 cells were essential for sustaining AHR but not for inducing acute disease, thereby implying a key role for IL-4/IL-4Rα signaling in perpetuating inflammation in the tissues. 36 …”

Section: Th2 Differentiation and T-cell Trafficking In Asthmatic Patimentioning

confidence: 99%

Pathogenic CD4 + T cells in patients with asthma

Muehling

Lawrence

Woodfolk

2017

Journal of Allergy and Clinical Immunology

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Asthma encompasses a variety of clinical phenotypes that involve distinct T cell–driven inflammatory processes. Improved understanding of human T-cell biology and the influence of innate cytokines on T-cell responses at the epithelial barrier has led to new asthma paradigms. This review captures recent knowledge on pathogenic CD4+ T cells in asthmatic patients by drawing on observations in mouse models and human disease. In patients with allergic asthma, TH2 cells promote IgE-mediated sensitization, airway hyperreactivity, and eosinophilia. Here we discuss recent discoveries in the myriad molecular pathways that govern the induction of TH2 differentiation and the critical role of GATA-3 in this process. We elaborate on how cross-talk between epithelial cells, dendritic cells, and innate lymphoid cells translates to T-cell outcomes, with an emphasis on the actions of thymic stromal lymphopoietin, IL-25, and IL-33 at the epithelial barrier. New concepts on how T-cell skewing and epitope specificity are shaped by multiple environmental cues integrated by dendritic cell “hubs” are discussed. We also describe advances in understanding the origins of atypical TH2 cells in asthmatic patients, the role of TH1 cells and other non-TH2 types in asthmatic patients, and the features of T-cell pathogenicity at the single-cell level. Progress in technologies that enable highly multiplexed profiling of markers within a single cell promise to overcome barriers to T-cell discovery in human asthmatic patients that could transform our understanding of disease. These developments, along with novel T cell–based therapies, position us to expand the assortment of molecular targets that could facilitate personalized treatments.

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Interleukin-2-Dependent Allergen-Specific Tissue-Resident Memory Cells Drive Asthma

Cited by 231 publications

References 60 publications

ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses

ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses

Do Memory CD4 T Cells Keep Their Cell-Type Programming: Plasticity versus Fate Commitment?

Pathogenic CD4 + T cells in patients with asthma

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