Development of Asthma in Inner-City Children: Possible Roles of MAIT Cells and Variation in the Home Environment

Abstract

Humans have populations of innate-like T lymphocytes with an invariant TCR α-chain that recognize nonpeptide Ags, including invariant NKT (iNKT) cells and mucosal-associated invariant T (MAIT) cells. iNKT cell involvement in human asthma is controversial, whereas there has been little analysis of MAIT cells. Using peripheral blood cells from 110 participants from the Urban Environment and Childhood Asthma (URECA) birth cohort study, these cells were analyzed for number and function. We determined whether iNKT cell or MAIT cell frequency at 1 y is correlated with the cytokine polarization of mainstream CD4+ T cells and/or the development of asthma by age 7 y. Dust samples from 300 houses were tested for iNKT cell antigenic activity. Our results show that a higher MAIT cell frequency at 1 y of age was associated with a decreased risk of asthma by age 7 y. The frequency of MAIT cells was associated with increased production of IFN-γ by activated CD4+ T cells from the URECA cohort. iNKT cell antigenic activity in bedroom dust samples was associated with higher endotoxin concentration and also with reduced risk of asthma. In conclusion, MAIT cell frequency at 1 y may reflect the tendency of the immune system toward Th1 responses and is associated with protection from asthma. Additionally, iNKT cell antigenic activity may be a marker of houses with increased microbial exposures and therefore also with protection from asthma.

Conflict of interest statement

Conflict of interest: The authors declare that they have no conflicts of interest.

Copyright © 2018 by The American Association of Immunologists, Inc.

Figures

Fig 1. Correlation of MAIT cells with CD4+ T cells producing IFNγ or IL-4

Pearson correlations were determined between MAIT cells as a percentage of total CD3+ cells and cytokine production in the indicated CD4+ T cell populations. Correlation coefficients and p-values are indicated below the plot (n = 110).

Fig 2. Association of iNKT and MAIT cell frequency with clinical outcomes

A comparison of the percentage of iNKT cells, of total CD3+ cells, in one year-old children that did or did not show aeroallergen sensitization at age 3 years (Neg, n = 60, Pos, n = 44) (a), recurrent wheezing at age 3 years (Neg, n = 78, Pos, n = 26) (b), and asthma (c) at age 7 years (Neg, n = 77, Pos, n = 18). MAIT cell percentage in one year-olds were compared to subsequent development of (d) aeroallergen sensitization at age 3 years (Neg n = 60, Pos n = 44), (e) recurrent wheezing at age 3 years (Neg, n = 78, Pos, n = 26), and (f) asthma at age 7 years (Neg, n = 77, Pos, n = 18). p-values were calculated using a Student’s t-test.

Fig 3. Cytokine production by iNKT and MAIT cells

Representative flow cytometry data for gated iNKT cells (a) and MAIT cells (b) activated with PMA and ionomycin and then analyzed by intracellular cytokine staining. Data from one of many similar analyses shown, see also Supplemental Figure 3 for compiled results for iNKT and MAIT cells.

Fig 4. HDEs from different houses vary in their antigenic activity

iNKT cell antigenic activity (IL-2 release) of URECA HDEs (n = 300) grouped by the magnitude of cytokine release in 10 pg/ml intervals (0-10, 11-20, etc.).

Fig 5. Endotoxin in bedroom is correlated with the amount of iNKT cell antigenic content in HDEs

Pearson correlation was determined between endotoxin from the bedrooms of children at age 3 months and the iNKT cell antigenic content in HDEs.

Fig 6. The frequency of iNKT cells is not correlated with the amount of iNKT cell antigen in HDEs

Pearson correlation was determined between the frequency of iNKT cells in peripheral blood, measured as a percentage of total CD3+ cells, and the antigenic content in HDEs.

Fig 7. Association of HDE antigenic activity with clinical outcomes

iNKT cell antigenic activity (IL-2 release) in URECA HDEs at 3 months of age was compared to aeroallergen sensitization at age 3 (Neg, n = 152, Pos, n = 125) (a), recurrent wheezing at age 3 (Neg, n = 184, Pos, n = 93) (b) and asthma (c) at age 7 (Neg, n = 181, Pos, n = 67). p-values were calculated using Student’s t-test.