Crucial role for CD69 in allergic inflammatory responses: CD69‐Myl9 system in the pathogenesis of airway inflammation

Abstract

CD69 has been known as an early activation marker of lymphocytes; whereas, recent studies demonstrate that CD69 also has critical functions in immune responses. Early studies using human samples revealed the involvement of CD69 in various inflammatory diseases including asthma. Moreover, murine disease models using Cd69 mice and/or anti-CD69 antibody (Ab) treatment have revealed crucial roles for CD69 in inflammatory responses. However, it had not been clear how the CD69 molecule contributes to the pathogenesis of inflammatory diseases. We recently elucidated a novel mechanism, in which the interaction between CD69 and its ligands, myosin light chain 9, 12a and 12b (Myl9/12) play a critical role in the recruitment of activated T cells into the inflammatory lung. In this review, we first summarize CD69 function based on its structure and then introduce the evidence for the involvement of CD69 in human diseases and murine disease models. Then, we will describe how we discovered CD69 ligands, Myl9 and Myl12, and how the CD69-Myl9 system regulates airway inflammation. Finally, we will discuss possible therapeutic usages of the blocking Ab to the CD69-Myl9 system.

Role of CD1d- and MR1-Restricted T Cells in Asthma

“…We recently identified myosin light chain (Myl) 9 and Myl12 as functional ligands for CD69 (45). We also showed that the interaction between CD69 on Th2 cells and Myl9 expressed on the luminal side of endothelial cells in the blood vessels recruits activated Th2 cells to the inflammatory site, resulting in airway inflammation (45, 46). CD69 on iNKT cells might therefore induce the migration of iNKT cells to the lung by binding to Myl9 or Myl12 and also play a critical role in the development of AHR and airway inflammation (Figure 1).…”

Targeting immunotherapy for bladder cancer using anti‐CD3× B7‐H3 bispecific antibody

“…Furthermore, FACS analysis showed increased CD69 expression on B7‐H3Bi‐Ab‐ATC over their unarmed ATC counterpart after 18‐hour incubation with T24 and T24/DDP cells (Figure B). CD69 has been known as an early activation marker of lymphocytes and has critical functions in immune responses . Increased CD69 expression on B7‐H3Bi‐Ab‐ATC proved that ATC was activated by B7‐H3Bi‐Ab.…”

“…CD69 has been known as an early activation marker of lymphocytes and has critical functions in immune responses. 33 Increased CD69 expression on B7-H3Bi-Ab-ATC proved that ATC was activated by B7-H3Bi-Ab. We used the same experiment in unactivated PBMCs.…”

Introduction to “allergic inflammation”

“…Th2 or Th17 cells infiltrate into the small vessels of the inflamed lung, re‐express CD 69 and interact with the CD 69 ligand Myl9, which is located at the luminal surface of small vessels and forms net structures (Myl9 net) in the vessels in inflamed lungs. Such CD 69‐Myl9 interaction may help the infiltration of antigen‐specific Th2 cells into the inflamed lung . Upon antigen stimulation, the infiltrated Th2 cells produce IL ‐4, IL ‐5, and IL ‐13 to induce eosinophilic inflammation, mucus hyper production and airway hyperreactivity.…”

“…Such CD69-Myl9 interaction may help the infiltration of antigen-specific Th2 cells into the inflamed lung. 29,30 Upon antigen stimulation, the infiltrated Th2 cells produce IL-4, IL-5, and IL-13 to induce eosinophilic inflammation, mucus hyper production and airway hyperreactivity. Th17 cells induce neutrophilic inflammation, which is steroid-resistant.…”