Differences in allergen-induced T cell activation between allergic asthma and rhinitis: Role of CD28, ICOS and CTLA-4

Abstract

Background: Th2 cell activation and T regulatory cell (Treg) deficiency are key features of allergy. This applies for asthma and rhinitis. However with a same atopic background, some patients will develop rhinitis and asthma, whereas others will display rhinitis only. Co-receptors are pivotal in determining the type of T cell activation, but their role in allergic asthma and rhinitis has not been explored. Our objective was to assess whether allergen-induced T cell activation differs from allergic rhinitis to allergic rhinitis with asthma, and explore the role of ICOS, CD28 and CTLA-4.

Methods: T cell co-receptor and cytokine expressions were assessed by flow cytometry in PBMC from 18 house dust mite (HDM) allergic rhinitics (R), 18 HDM allergic rhinitics and asthmatics (AR), 13 non allergic asthmatics (A) and 20 controls, with or without anti-co-receptors antibodies.

Results: In asthmatics (A+AR), a constitutive decrease of CTLA-4+ and of CD4+CD25+Foxp3+ cells was found, with an increase of IFN-γ+ cells. In allergic subjects (R + AR), allergen stimulation induced CD28 together with IL-4 and IL-13, and decreased the proportion of CTLA-4+, IL-10+ and CD4+CD25+Foxp3+ cells. Anti-ICOS and anti-CD28 antibodies blocked allergen-induced IL-4 and IL-13. IL-13 production also involved CTLA-4.

Conclusions: T cell activation differs between allergic rhinitis and asthma. In asthma, a constitutive, co-receptor independent, Th1 activation and Treg deficiency is found. In allergic rhinitis, an allergen-induced Treg cell deficiency is seen, as well as an ICOS-, CD28- and CTLA-4-dependent Th2 activation. Allergic asthmatics display both characteristics.

Figure 1

T cell activation and co-receptor expression before specific stimulation. CTLA-4 expression (A), Treg cells (CD4+CD25+^HiFoxp3+, B), IFN-γ producing T cells (D) and ICOS expression (E) were assessed by flow cytometry in PBMC from HDM allergic rhinitics (R) (triangle, n = 18), allergic asthmatics and rhinitics (AR) (square, n = 18), non allergic asthmatics (A) (lozenge, n = 13), and controls (circle, n = 20). Treg cells were also evaluated in non allergic asthma and allergic asthma between mild and moderate asthmatics (C). Results are expressed as percentage of total T cell and compared versus controls. _ : mean of each group. * = p < 0.05; ** = p < 0.01

Figure 2

T cell activation and co-receptor expression after specific stimulation. ICOS, CTLA-4 expression, IL-4, IL-13, IL-10 producing T cells and Treg cells (CD4+CD25+^HiFoxp3+) were assessed by flow cytometry in PBMC from HDM allergic asthmatics and rhinitics (AR) (A, n = 18), HDM allergic rhinitics (R) (B, n = 18), non allergic asthmatics (A) (C, n = 13), and controls (D, n = 20) stimulated or not with Derp1 allergen (1 μg/ml) during 8 days. Results are expressed as percentage of total T cells. _ : mean of each group. * = p < 0.05; ** = p < 0.01

Figure 3

Effect of anti-co-receptors antibodies on IL-13 production by T cells. PBMC from allergic rhinitics (R) (triangle, n = 12), allergic rhinitic and asthmatics (AR) (square, n = 10) and non allergic asthmatics (A) (lozenge, n = 11) were stimulated with Derp 1 and cultured in the presence or absence of anti-ICOS, anti-CTLA-4 or anti-CD28 antibodies. IL-13 expressing T cells were then compared in each group versus baseline. Results are expressed as percentage of total T cells. Black line : mean of each group. * = p < 0.05; ** = p < 0.01; *** = p < 0.001