Abstract
CD4+ T regulatory cells (Tregs) comprise a heterogeneous population of cells the regulate immune responses and prevent autoimmunity. Most reports on human Tregs are derived from studies of peripheral blood, although Tregs mainly exert their functions in the periphery. Here we performed a detailed analysis of Tregs in the human upper airway mucosa under non-inflammatory conditions, and found that 10% of all CD4+ T cells expressed the transcription factor FOXP3 and the memory marker CD45RO, as well as high levels of CTLA-4. The majority of FOXP3+CD4+ T cells co-expressed the transcription factor Helios and produced very little cytokines, compatible with being thymus-derived Tregs. FOXP3+Helios-CD4+ T cells were more heterogeneous. A mean of 24% produced the immunomodulatory cytokine IL-10, whereas a large fraction also produced IL-2, IFN-μ or IL-17. A significant population (6%) of FOXP3-negative T cells also produced IL-10, usually in combination with IFN-μ. Together, we found that CD4+ T cells in the upper airways differed functionally from their counterparts in peripheral blood, including higher expression of IL-10. Moreover, our findings suggest that several subsets of CD4+ T cells with functionally distinct regulatory properties reside in the upper airway mucosa which should be taken into account when targeting Tregs for therapy.
Highlights
The environment of the respiratory tract is extremely challenging for the local immune system [1]
We found that a mean of 95% of CD4+ T cells in the nasal mucosa expressed the memory marker CD45RO, whereas 54% of CD4+ T cells were CD45RO-positive in peripheral blood (Fig 1A and 1B)
Similar to FOXP3+ T regulatory cells (Tregs) in peripheral blood [4], we found that the vast majority of FOXP3 +CD4+ T cells in the nasal mucosa were CD127-negative (Fig 2A)
Summary
The environment of the respiratory tract is extremely challenging for the local immune system [1]. The upper airway mucosa is constantly exposed to a vast variety of harmless, but highly antigenic proteins of plant or animal origin. Maintenance of homeostasis in the airways depends on the ability of the local immune system to be tolerant to such antigens, while at the same time be able to rapidly mount an immune response to microbial pathogens, including a large array of viruses, which use the upper airway mucosa as their primary entry site. Breakdown of tolerance mechanisms to otherwise harmless antigens may lead to unwanted chronic inflammatory reactions, such as allergic rhinitis, which affects more than 20% of the population in industrialized countries [2].
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