Th2A cells: The pathogenic players in allergic diseases

Abstract

Proallergic type 2 helper T (Th2A) cells are a subset of memory Th2 cells confined to atopic individuals, and they include all the allergen-specific Th2 cells. Recently, many studies have shown that Th2A cells characterized by CD3⁺ CD4⁺ HPGDS⁺ CRTH2⁺ CD161^high ST2^high CD49d^high CD27^low play a crucial role in allergic diseases, such as atopic dermatitis (AD), food allergy (FA), allergic rhinitis (AR), asthma, and eosinophilic esophagitis (EoE). In this review, we summarize the discovery, biomarkers, and biological properties of Th2A cells to gain new insights into the pathogenesis of allergic diseases.

Keywords: CD161; CRTH2; HPGDS; ST2; Th2A cells; allergen-specific Th2 cells; allergic disease.

Figure 1

The signaling pathway of Th2A cells. The interaction of ST2 with IL-33 recruits MYD88 to activate TRAF6 by IRAK, leading to the activation of NF-kB released from the IKK complex. After CD161 combination with LLT1, aSMase is recruited to catalyze SM into ceramide, resulting in the aggregation in the membrane and inside the cells to mediate distinct functions. CRTH2 activated by PGD2 reduces cAMP production, thereby inhibiting NF-κB activity and phosphorylates CREB protein. Meanwhile, the same as TCR, CRTH2 also activates PKCθ, ERK/MAPK, and Ca2⁺ calcineurin signaling pathways to mediate cell survival, proliferation, and cytokine production through the transcription factor NF-κB, AP-1, and NFAT. Arachidonic acid derived from phospholipids is converted to PGH2 by COX-1/2, which can then be catalyzed into PGD2 by HPGDS. IKK, IκB kinase; ZAP70, ζ-chain associated protein kinase of 70 kDa; PLCγ, phospholipase Cγ; PIP2, phosphatidylinositol bisphosphate; DAG, diacylglycerol; PKCθ, protein kinase Cθ; RASGRP, RAS guanyl nucleotide–releasing protein; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; IP3, inositol trisphosphate; cAMP, cyclic adenosine 3, 5′-monophosphate; PKA, protein kinase A; COX-1/2, cyclooxygenases I and II; ASM, acid sphingomyelinase; CaN, calcineurin.

Figure 2

Th2A cells’ biological function. After allergen stimulation, epithelial cells secrete IL-25, IL-33, and TSLP to activate APCs and Th2A cells. APCs present allergens to activate tissue-resident Th2A cells. Th2A cells that have been activated secrete IL-5 and IL-9, which aid in the recruitment and activation of eosinophils. Th2A cells produce IL-4 and IL-13, stimulating B cells to produce allergen-specific IgE antibodies. Meanwhile, Th2A cells secrete IL-4, IL-9, and IL-10 to activate mast cells and basophils.