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

Abstract

BackgroundTh2 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.MethodsT 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.ResultsIn 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.ConclusionsT 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.

Impaired ICOSL in human myeloid dendritic cells promotes Th2 responses in patients with allergic rhinitis and asthma

“…In this study of myeloid DCs from AR patients, we could link the aberrant pro-Th2 capacity (induction of IL-13 and IL-5) of DCs to ICOSL downregulation. Previous studies in mice [16,17] showed that ICOSL/ICOS interactions between DC and T cells lead to Th2 responses, and up-regulated ICOS in PBMC from AR patients underlined Th2 responses [18]. However, ICOS/ICOSL interaction also leads to Treg generation [17], as well as CD8a À DCs expressing higher ICOSL and IL-10 [27].…”

House dust allergy and immunotherapy

“…Increased IFN-γ release by both CD4+ and CD8+ T-cells from allergic adults was then found for responses to Der p 1 74 and then for children where there was a positive association with bronchial hyper-reactivity 75 , 76 . Botturi et al now report that peripheral blood mononuclear cells from asthmatics respond to purified lipopolysaccharide (LPS)-free Der p 1 by generating more IFN-γ producing T cells than cells from healthy subjects 77 and the recent comparison of tetramer staining of T-cells from HDM and birch-pollen allergic patients showed that in comparison to Bet v 1-binding cells, HDM-allergen-binding cells displayed a wide range of cytokines including IFN-γ 69 . There are reports indicating that T-cell from asthmatics with protracted HDM sensitization may have reduced IFN-γ 78 , 79 but there is growing realization of a contribution of Th1 responses to the pathogenesis of allergic disease 63 , 64 …”

“…Immunoregulatory IL-10 producing cells are increased after immunotherapy 52 and after repeated bee stings 80 but natural control of inhalant allergy by IL-10 is unclear, 81 , 82 especially for HDM where increased IL-10 production is found in responses of allergic subjects to allergens 75 , 77 , 83 and extracts, 82 , 84 , 85 including highly purified LPS-free Der p 1 77 . This might be the concomitant production of effector and regulatory responses since Heaton et al showed an inverse relationship between the size of skin test responses and IL-10 production 75 .…”

“…Der p 1-specific CD4+CD25+Foxp3+ with in vitro suppressor functions have been generated by extended in vitro culture with allergen but from both nonatopic and HDM allergic individuals 88 . Botturi et al also found no defect of CD4+CD25+Foxp3+ cells in HDM-allergic subjects with or without Der p 1 stimulation 77 . Going further, increased expression of HDM-extract-induced Foxp3 transcripts has been demonstrated from CD4+CD25+ cells of infants with atopic dermatitis 89 and increased numbers of nTregs have been demonstrated in asthmatic children 90 .…”

Comparing the effects of two inhaled glucocorticoids on allergen‐induced bronchoconstriction and markers of systemic effects, a randomised cross‐over double‐blind study

“…This argues that both drugs and the doses tested are sufficient to efficiently attenuate the inflammatory response associated with the late asthmatic response, as has been previously documented [2,9,18]. The exact mechanism by which inhaled glucocorticoids have such pronounced effect on eosinophilic inflammation are not clear, although inhibitory effects on T-lymphocyte responses may be crucial [19]. …”