Protective role of nuclear factor of activated T cells 2 in CD8(+) long-lived memory T cells in an allergy model

Background: The transcriptional regulation of cytokines released and controlled by memory T cells is not well understood. Defective IFN-gamma production in allergic asthma correlates in human beings with the risk of wheezing in childhood. Objective: To understand the role of the transcription factor nuclear factor of activated T cells 2 (NFATc2) in memory and effector T cells in the airways in experimental allergic asthma. Methods: We used murine models of allergic asthma and adoptive cell transfer of fluorescence-activated sorted cells in a disease model. Results: Mice lacking NFATc2 developed an increase in airway hyperresponsiveness (AHR), remodeling, and serum IgE levels on ovalbumin sensitization. This phenotype was associated with CD8(+)CD122(-) T cells deficient in IFN-gamma production in the airways. The origin of this phenotype in NFATc2((-/-)) mice was related to an expanded population of lung CD8(+)CD122(+) (IL-2R beta chain) CD127(hi) (IL-7 receptor [R] alpha chain(+)) long-lived memory cells. Adoptive transfer of ovalbumin-specific CD8(+) NFATc2((-/-)) T cells enhanced the AHR generated by NFATc2((-/-)) CD4(+) T cells in immunodeficient mice, increased IL-17, and reduced IFN-gamma production in the reconstituted mice. Depletion of the memory CD8(+)CD122(+)IL-7R(high) T-cell population corrected the defect in IFN-gamma production by lung NFATc2((-/-)) CD8(+)CD122(+) cells and abrogated the increased AHR observed in NFATc2((-/-)) CD8(+) T-cell-reconstituted mice with a severe combined immunodeficiency disorder. Conclusion: Taken together, our results suggest that NFATc2 expression in long-lived memory CD8(+) T cells controls IL-2 and IFN-gamma production in lung CD8(+) T cells, which then limits T(H)17 and T(H)2 development in the airways during allergen challenge.