IL-4-, TGF-β-, and IL-1-dependent expansion of parasite antigen-specific Th9 cells is associated with clinical pathology in human lymphatic filariasis

• Published in: The Journal of immunology (1950) 2013-09, Vol.191 (5), p.2466-2473
• Main Authors: Anuradha, Rajamanickam, George, Parakkal Jovvian, Hanna, Luke E, Chandrasekaran, Vedachalam, Kumaran, Paul, Nutman, Thomas B, Babu, Subash
• Format: Article
• Language: English
• Subjects: CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Elephantiasis, Filarial - immunology; Elephantiasis, Filarial - metabolism; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-1 - immunology; Interleukin-1 - metabolism; Interleukin-10 - biosynthesis; Interleukin-10 - immunology; Interleukin-4 - immunology; Interleukin-4 - metabolism; Interleukin-9 - biosynthesis; Interleukin-9 - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1300911

Th9 cells are a subset of CD4(+) T cells, shown to be important in allergy, autoimmunity, and antitumor responses; however, their role in human infectious diseases has not been explored in detail. We identified a population of IL-9 and IL-10 coexpressing cells (lacking IL-4 expression) in normal individuals. These cells respond to antigenic and mitogenic stimulation, but are distinct from IL-9(+) Th2 cells. We also demonstrate that these Th9 cells exhibit Ag-specific expansion in a chronic helminth infection (lymphatic filariasis). Comparison of Th9 responses reveals that individuals with pathology associated with filarial infection exhibit significantly expanded frequencies of filarial Ag-induced Th9 cells, but not of IL9(+)Th2 cells in comparison with filarial-infected individuals without associated disease. Moreover, the per cell production of IL-9 is significantly higher in Th9 cells compared with IL9(+)Th2 cells, indicating that the Th9 cells are the predominant CD4(+) T cell subset producing IL-9 in the context of human infection. This expansion was reflected in elevated Ag-stimulated IL-9 cytokine levels in whole blood culture supernatants. Finally, the frequencies of Th9 cells correlated positively with the severity of lymphedema (and presumed inflammation) in filarial-diseased individuals. This expansion of Th9 cells was dependent on IL-4, TGF-β, and IL-1 in vitro. We have therefore identified an important human CD4(+) T cell subpopulation coexpressing IL-9 and IL-10, but not IL-4, the expansion of which is associated with disease in chronic lymphatic filariasis and could potentially have an important role in the pathogenesis of other inflammatory disorders.