Increased activation-induced cell death of high IFN-γ–producing T_H1 cells as a mechanism of T_H2 predominance in atopic diseases

Background

A dysregulated and T_H2-biased immune response appears to be a key pathogenetic factor in atopic diseases. Increased activation and massive infiltration of T cells in the dermis without any evidence for the expansion of their numbers in peripheral blood characterize atopic dermatitis.

Objective

To investigate differences and mechanisms of T_H1 and T_H2 cell activation-induced cell death (AICD) in atopic disease.

Methods

Naive (CD4⁺CD45⁺RA) and memory (CD4⁺CD45⁺RO) T cells were isolated from healthy and atopic individuals. T_H1 and T_H2 subsets were in vitro differentiated. High IFN-γ–producing T cells and CXCR3⁺ T cells were purified, and AICD of isolated cells was determined in addition to expression of apoptosis receptors and caspase activation.

Results

T_H1 cells, particularly their high IFN-γ–producing fraction, and CXCR3⁺ T cells showed significantly increased apoptosis in atopic individuals. During their in vitro differentiation, both T_H1 and T_H2 cells of atopic individuals showed increased apoptosis compared with the healthy control group, with a significantly high apoptosis in T_H1 cells. Increased expression of Fas, Fas-ligand, tumor necrosis factor receptor-II, and caspase activation was detected on T_H1 cells that underwent apoptosis. Neutralization experiments demonstrated a dominant role of IFN-γ and Fas–Fas-ligand interaction-mediated suicide in T_H1 cell AICD.

Conclusion

Predominant T_H2 profile in atopic diseases might be a result of the increased tendency to activation and apoptosis of high IFN-γ–producing T_H1 cells.

Key words: T cells, activation-induced cell death, apoptosis, atopy, T_H1 cells, CXCR3

Abbreviations used: 7AAD, 7-Amino-actinomycin D, AD, Atopic dermatitis, AICD, Activation-induced cell death, CLA, Cutaneous lymphocyte–associated antigen