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-γ 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-γ production in the airways. The origin of this phenotype in NFATc2 (−/−) mice was related to an expanded population of lung CD8 + CD122 + (IL-2Rβ chain) CD127 hi (IL-7 receptor [R] α 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-γ production in the reconstituted mice. Depletion of the memory CD8 + CD122 + IL-7R high T-cell population corrected the defect in IFN-γ 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-γ production in lung CD8 + T cells, which then limits T H 17 and T H 2 development in the airways during allergen challenge.