Antiapoptotic serine protease inhibitors contribute to survival of allergenic TH2 cells

    loading  Checking for direct PDF access through Ovid

Abstract

Background:

The mechanisms that regulate maintenance of persistent TH2 cells and potentiate allergic inflammation are not well understood.

Objective:

The function of serine protease inhibitor 2A (Spi2A) was studied in mouse TH2 cells, and the serine protease inhibitor B3(SERPINB3)andSERPINB4genes were studied in TH2 cells from patients with grass pollen allergy.

Methods:

Spi2A-deficient TH2 cells were studied inin vitroculture orin vivoafter challenge of Spi2A knockout mice with ovalbumin in alum. Expression ofSERPINB3andSERPINB4mRNA was measured inin vitro–cultured TH2 cells and inex vivoCD27−CD4+ cells and innate lymphoid cell (ILC) 2 from patients with grass pollen allergy by using quantitative PCR.SERPINB3andSERPINB4mRNA levels were knocked down in cultured CD27−CD4+ cells with small hairpin RNA.

Results:

There were lower levels ofin vitro–polarized TH2 cells from Spi2A knockout mice (P< .005) andin vivoafter ovalbumin challenge (P< .05), higher levels of apoptosis (Annexin V positivity,P< .005), and less lung allergic inflammation (number of lung eosinophils,P< .005).In vitro–polarized TH2 cells from patients with grass pollen allergy expressed higher levels of bothSERPINB3andSERPINB4mRNA (bothP< .05) compared with unpolarized CD4 T cells. CD27−CD4+ from patients with grass pollen allergy expressed higher levels of bothSERPINB3andSERPINB4mRNA (bothP< .0005) compared with CD27+CD4+ cells. ILC2 expressed higher levels of bothSERPINB3andSERPINB4mRNA (bothP< .0005) compared with ILC1. Knockdown of eitherSERPINB3orSERPINB4mRNA (bothP< .005) levels resulted in decreased viability of CD27−CD4+ compared with control transduced cells.

Conclusion:

The Serpins Spi2A in mice and SERPINB3 and SERPINB4 in allergic patients control the viability of TH2 cells. This provides proof of principle for a therapeutic approach for allergic disease through ablation of allergic memory TH2 cells throughSERPINB3andSERPINB4mRNA downregulation.

Related Topics

    loading  Loading Related Articles