Chronic Inflammation in Asthma: Looking Beyond the Th2 Cell

Abstract

Asthma is a common chronic inflammatory disease of the airways. A substantial number of patients present with severe and therapy-resistant asthma, for which the underlying biological mechanisms remain poorly understood. In most asthma patients, airway inflammation is characterized by chronic activation of type 2 immunity. CD4⁺ T helper 2 (Th2) cells are the canonical producers of the cytokines that fuel type 2 inflammation: interleukin (IL)-4, IL-5, IL-9, and IL-13. However, more recent findings have shown that other lymphocyte subsets, in particular group 2 innate lymphoid cells (ILC2s) and type 2 CD8⁺ cytotoxic T (Tc2) cells, can also produce large amounts of type 2 cytokines. Importantly, a substantial number of severe therapy-resistant asthma patients present with chronic type 2 inflammation, despite the high sensitivity of Th2 cells for suppression by corticosteroids-the mainstay drugs for asthma. Emerging evidence indicates that ILC2s and Tc2 cells are more abundant in severe asthma patients and can adopt corticosteroid-resistance states. Moreover, many severe asthma patients do not present with overt type 2 airway inflammation, implicating non-type 2 immunity as a driver of disease. In this review, we will discuss asthma pathophysiology and focus on the roles played by ILC2s, Tc2 cells, and non-type 2 lymphocytes, placing special emphasis on severe disease forms.

Keywords: ILC2; Tc2 cell; Th2 cell; asthma; cytokines; type 2 inflammation.

FIGURE 1

Th2 cells, ILC2s and Tc2 cells as drivers of type 2‐high asthma pathophysiology. In type 2‐high asthma, triggers such as allergens but also viral infections damage and/or activate the lung epithelial cells (indicated by dashes cell outlines), which in turn secrete alarmins such as IL‐33, TSLP, and IL‐25. (A) Alarmins can activate dendritic cells (DCs), which can take up allergens and migrate to lymph nodes. Here, antigen presentation to naive T cells via major histocompatibility (MHC) class II—T cell receptor (TCR) interactions combined with IL‐4 signals from follicular T helper (Tfh) cells induce Th2 cell differentiation. Th2 cells migrate back to the lungs and start producing type 2 cytokines IL‐4, IL‐5, IL‐9, and IL‐13, which can be (1) further stimulated by alarmins, (2) regulated by ILC2 activity or (3) efficiently suppressed by corticosteroids. (B) Viral infections and alarmins can induce rapid local secretion of type 2 cytokines by activating lung‐resident ILC2s, which can further augment Th2 responses and can adopt steroid‐resistant phenotypes. (C) IL‐33, perhaps directly (dashed arrow) and/or via the induction of local IL‐4 production, may induce Tc1‐to‐Tc2 plasticity to increase local Tc2 cell abundance and type 2 cytokine production. Skewing of the lung Tc compartment to a Tc2 phenotype can be suppressed by conventional type 1 DCs (cDC1s) and IFNγ signaling. Allergen‐specific Tc2 responses (via a DC‐mediated lymph node response, also see A) may also play a role in generating Tc2 cells in the lung. Tc cells are generally considered more resistant to corticosteroids. The bottom panel depicts the downstream cellular targets of the type 2 cytokines, ultimately resulting in the hallmark symptoms of asthma indicated in the red box.

FIGURE 2

Overview of specific immune responses and key lymphocyte subsets involved. Different types of immune challenges induce responses driven by specific innate lymphoid cell (ILC), CD4⁺ T helper (Th) and CD8⁺ cytotoxic T (Tc) cell subsets. For each type of challenge, ILC and T cell counterparts rely on the same lineage‐specifying transcription factor (i.e., T‐BET, GATA3, RORγ or EOMES) to converge on the production of specific effector cytokines or granzymes (“key output”). Th‐c cells are CD4⁺ Th cells with cytotoxic properties. Tc1 cells depend on both T‐BET and EOMES.

FIGURE 3

Key signaling pathways regulating ILC2 activity. (A) IL‐33 binds to a receptor heterodimer that consists of an ST2 and an IL‐1RAcP subunit. IL‐25 also binds a receptor heterodimer but instead composed of IL‐17RA and IL‐17RB. Signaling via both receptors leads to downstream activation of NF‐kB and MAPK pathways. MAPK signaling subsequently triggers AP‐1 activation, which can occur via phosphorylation (as depicted) but also through de novo transcription of AP‐1 family genes (not shown). As a result, NF‐κB and AP‐1 transcription factors bind DNA and promote the transcription of the type 2 cytokine genes. Additionally, MAPK proteins can induce phosphorylation of GATA3, facilitating its binding to IL5 and IL13 gene promoters to enhance transcription. (B) IL‐2 (IL‐2R) and IL‐7 (IL‐7R) receptor subunits pair with the common γ chain (γc). Activation of these receptor heterodimers leads to phosphorylation of the JAK1 and JAK3 kinases. JAK1/JAK3 subsequently bind and phosphorylate cytoplasmic STAT proteins—most prominently STAT5. Phosphorylated STAT5 dimerizes and translocates to the nucleus, where it acts as a transcription factor that activates the type 2 cytokine locus and but also enhances GATA3 transcription. Elevated GATA3 levels results in further induction of type 2 cytokine gene transcription, but also promotes IL1RL1 (encoding ST2) expression. The alarmin TSLP signals via a heterodimeric receptor consisting of TSLP receptor (TSLPR) and IL‐7R subunits. Very similar to IL‐2 and IL‐7, TSLP signals trigger a JAK‐STAT5 signaling cascade that terminates in increased transcription of the type 2 cytokine genes.

FIGURE 4

Human inflammatory CD45RO⁺ ILC2s and severe type 2 respiratory disease. Resting human ILC2s express the CD45RA splicing isoform of the CD45 surface receptor. Upon combined exposure to alarmins such as IL‐33 or IL‐1β and a STAT5‐inducing cytokine (e.g., IL‐2, IL‐7), these CD45RA⁺ ILC2s convert into CD45RO⁺ ILC2s that are highly proliferative and secrete large amounts of type 2 cytokines. This CD45RA‐to‐RO conversion is tightly linked to the upregulation of the BATF and IRF4 transcription factors and can be effectively suppressed by corticosteroids. However, once converted, CD45RO⁺ ILC2s show reduced sensitivity to corticosteroids, and their abundance positively correlates with increased disease severity in asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) patient samples.

FIGURE 5

Lymphocyte differentiation and plasticity. The major differentiation routes from multi‐potent naive T helper (Th), T cytotoxic (Tc) and ILC progenitors (ILCP) are indicated by black arrows; arrow thickness in the Tc cell panel denotes that Tc1 differentiation is the dominant route. However, the identity of mature T cells and ILCs is not set in stone: microenvironmental signals such as cytokines can destabilize lymphocyte identity, resulting in the acquisition of functional characteristics (e.g., cytokine production) otherwise restricted to other subsets—a phenomenon referred to as plasticity (red arrows). Particularly plastic among lymphocytes are Th17 cells and ILC2s. Not all possible routes for plasticity are indicated; we focused on those supported by substantial evidence and of potential relevance to asthma.