Pathogenic CD4+ T cells in patients with asthma

Abstract

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, T_H2 cells promote IgE-mediated sensitization, airway hyperreactivity, and eosinophilia. Here we discuss recent discoveries in the myriad molecular pathways that govern the induction of T_H2 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 T_H2 cells in asthmatic patients, the role of T_H1 cells and other non-T_H2 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.

Keywords: Asthma; GATA-3; IL-25; IL-33; IgE; T(H)1; T(H)17; T(H)2; T(H)22; T-bet; T-cell epitopes; T-cell plasticity; allergens; epithelial barrier; follicular helper T cell; thymic stromal lymphopoietin.

FIG 1

Molecular events in T_H2 differentiation. A, DCs act as a hub for T_H2 licensing. T_H2 differentiation is orchestrated by integration of diverse external cues that generate a T_H2-permissive cytokine milieu in conjunction with an array of receptor/ligand interactions at the T-cell surface. IDO, Indoleamine 2,3-dioxygenase; IL-25R, IL-25 receptor; KLF4, Kruppel-like factor 4; PRR, pattern recognition receptor; TLR4, Toll-like receptor 4; TSLPR, TSLP receptor. B, Within T_H2 cells, differentiation is orchestrated by the IL-4–induced GATA-3 pathway, as well as other pathways, that coordinate increased accessibility of T_H2 cytokine gene loci and promote their transcription. MAML1, Mastermind-like protein 1; RBPJ, recombination signal binding protein for immunoglobulin kappa J region; Sox4, Sry-related high-mobility-group box 4; TCF-1, T-cell factor 1.

FIG 2

T_H2-promoting cytokine networks at the epithelial barrier. Left panel, Innate cytokines triggered by environmental stimuli induce T_H2 licensing of DCs and their migration to the draining lymph nodes. Rapid activation of ILC2 cells promotes eosinophil recruitment and DC migration. Right panel, Antigen-experienced effector (CCR7⁻) T_H2 cells are recruited to inflamed sites through CCR4 ligands (CCL17 and CCL22) secreted by TSLP-activated DCs, where they respond to direct and indirect effects of innate and T_H2 cytokines. Inflammation is perpetuated by mechanisms that promote a “leaky” barrier through modulation of structural proteins. Egress or “spillover” of T_H2 cells from inflamed sites results in their recirculation and possible reversion to central memory status (CCR7⁺). cDC2, Conventional type 2 myeloid dendritic cell; HDAC, histone deacetylase.

FIG 3

Schematic of an MHCII tetramer. Peptide epitopes bind to MHCII molecules through interactions between side chains of anchor residues and MHC pockets of the peptide-binding groove. Synthetic multimeric peptide/MHCII complexes bind to antigen-specific CD4⁺ T cells with high avidity.

FIG 4

CD4⁺ T_H types linked to asthma. Distinct T_H subsets differentiate from naive CD4⁺ T cells in response to different inductive cytokines. Each T_H subset bears a characteristic molecular signature defined by lineage-specifying transcription factors, surface chemokine receptors, and secreted cytokines. Atypical T_H types are also shown. The transcription factor profile of T_H2/T_H22 cells is unknown. AhR, Aryl hydrocarbon receptor; RORγt, retinoic acid–related orphan receptor γt.

FIG 5

Tools for T-cell discovery in asthma. New technologies enable highly multiplexed analysis of selected T-cell populations or single cells. These “omics” approaches capture large amounts of data at the genetic/epigenetic, gene transcript, and protein levels, which are then deciphered by using bioinformatic pipelines. Emerging computational tools will integrate these data with other clinical and immune parameters to inform new research directions and treatments. RNA-seq, RNA sequencing.

FIG 6

T cell–based therapeutic strategies. A, Peptide-based immunotherapy suppresses T_H2 responses without inducing adverse sequelae mediated by IgE receptor cross-linking. B, Effect of mAb therapies on T_H2 effector functions. *Clinical trials in progress. C, Emerging molecular therapeutics for allergic asthma.