The Unique Features of Th9 Cells and their Products

Abstract

Although it was discovered more than two decades ago, new information concerning the biological activities of IL-9 has been provided in recent years, after the isolation of cells that selectively produce this cytokine, designated “Th9.” Th9 cells are generated in vitro by polarization, mainly by TGF-β and IL-4, during activation with the specific antigen, or with anti-CD3/CD28 antibodies. This review deals mainly with Th9 generated by the former, “physiological” mode of activation. Of particular interest is the unique production kinetics of IL-9: the cytokine is produced very rapidly, but after reaching its peak (day 3 in our studies), it declines sharply to trace levels. In addition to IL-9, Th9 cells also produce similar amounts of another cytokine, IL-10, but the production kinetics of these two cytokines are strikingly different. Antigen-activated Th9 in our studies also developed pathogenic capacity, but only during the short time period of peak IL-9 production. Interestingly, no IL-9-producing cells were detected in sites of inflammation induced by Th9, in contrast to Th1 and Th17. The unique features of Th9 cells and their products are discussed with regards to the known and assumed functions of the cytokine.

Phenotypes of Th lineages generated by the commonly used activation with anti-CD3/CD28 antibodies differ from those generated by the physiological activation with the specific antigen

“…Unlike Th17, Th9 cells were consistently pathogenic only when activated by the Abs (PbAb). It is of note that moderate disease was induced by HA-activated Th9 cells, but only when collected on day 3 of incubation; no pathological changes were detected in eyes of recipients injected with cells collected on days 4 or 5 of incubation 6,16 . It is also noteworthy that large portions of adoptively transferred Th17 and Th9 shift their phenotype in the recipient mice and acquire new phenotype 15,16 .…”

T cell subsets and their signature cytokines in autoimmune and inflammatory diseases

“…It was initially viewed as a Th2 cell cytokine, however, more recently, IL-9 has been identified in a subset of T cells distinct from Th2 cells, now delineated as Th9 cells 164 . The development of Th9 cells requires the combination of TGF-β (which also promotes Tregs) and IL-4 (known to induce Th2 cells) 165 .…”

“…The development of Th9 cells requires the combination of TGF-β (which also promotes Tregs) and IL-4 (known to induce Th2 cells) 165 . Interestingly, Th9 cells, which are strongly associated with the immunopathology of asthma, also produce IL-10 164 .…”

Epigenetic dynamics during CD4+ T cells lineage commitment

“…The latter is also selectively produced by another subset called Th22 cells, but, unlike Th17 cells, express low levels of ROR␥t and high levels of T-bet (also produced by Th1 cells) (Eyerich et al, 2009;Trifari et al, 2009;Trifari and Spits, 2010). Additionally, a new subset named Th9 was identified from its production of IL-9 cytokine, which is also produced by Th2 cells, but in this case is regulated by a different TF, PU.1, in combination with IRF4 and GATA-3 (Goswami and Kaplan, 2012;Kaplan, 2013;Schmitt and Bopp, 2012;Tan and Gery, 2012). In addition to this complex picture, and in contrast to the previous criteria for defining lineages, a new subset known as follicular helper T (Tfh) cells was characterized on the basis of their localization in germinal centers (Crotty, 2011).…”