Tc9 cells, a new subset of CD8⁺ T cells, support Th2‐mediated airway inflammation

Abstract

Similar to T-helper (Th) cells, CD8+ T cells also differentiate into distinct subpopulations.However, the existence of IL-9-producing CD8 + T (Tc9) cells has not been elucidated so far. We show that murine CD8 + T cells activated in the presence of IL-4 plus TGF-β develop into transient IL-9 producers characterized by specific IFN-γ and IL-10 expression patterns as well as by low cytotoxic function along with diminished expression of the CTL-associated transcription factors T-bet and Eomesodermin. Similarly to the CD4 + counterpart, Tc9 cells required for their differentiation STAT6 and IRF4. Tc9 cells deficient for these master regulators displayed increased levels of Foxp3 that in turn suppressed IL-9 production. In an allergic airway disease model, Tc9 cells promoted the onset of airway inflammation, mediated by subpathogenic numbers of Th2 cells. This support was specific for Tc9 cells because CTLs failed to exert this function. We detected increased Tc9 frequency in the periphery in mice and humans with atopic dermatitis, a Th2-associated skin disease that often precedes asthma. Thus, our data point to the existence of Tc9 cells and to their supportive function in Th2-dependent airway inflammation, suggesting that these cells might be a therapeutic target in allergic disorders.Keywords: Allergic airway inflammation r Atopic dermatitis r CD8 + T cells r IL-9 r Tc9 cells Additional supporting information may be found in the online version of this article at the publisher's web-site 607Introduction IL-9 is a pleiotropic cytokine produced by different cell types such as T cells, innate lymphoid cells, eosinophils, and mast cells [1,2]. IL-9 secretion by T cells was originally linked to Th2-mediated (where Th is T-helper) diseases such as allergic airway inflammation [3,4] and parasite infection [5,6] However, in vitro IL-9 is differently regulated from other classical Th2-cytokines such as IL-4, IL-5, and IL-13. IL-9 is induced by the combination of the Th2-skewing cytokine IL-4 with TGF-β [7] and, under these conditions Th2-cytokines are strongly inhibited [8,9]. Therefore, besides Th1, Th2, Th17, and Treg cells, IL-9-producing cells have been established as an additional Th-cell subset, termed Th9 cells. The differentiation of Th9 cells is governed by the transcription factors IRF4, PU.1, and STAT6 [10,11]. IRF4, also important for Th2-, Th17-, and Tfh-fate decisions [12][13][14][15] regulates IL-9 production directly by binding to the Il9 promoter [10]. Likewise, PU.1 enhances IL-9 production, at least partly by binding to the Il9 promoter [11]. In contrast, STAT6, activated by IL-4, contributes to IL-9 production indirectly. It represses the expression of two transcription factors, Treg-specific Foxp3 and Th1-associated T-bet that inhibit IL-9 production [8,9,16].Similarly to Th cells, CD8 + T cells differentiate into at least four effector subsets with different phenotype: CTLs, Tc2, Tc17, or CD8 + Treg cells [17]. The best characterized CD8 + T-cell subpopulation, CTLs kill infected or tumorogenic cells ...

Tumor-specific IL-9–producing CD8+Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers

“…Apart from the differences in cytokine secretion, Tc9 cells differed from Tc1 cells in that they were less cytotoxic in vitro. In line with our observation, a recent publication also confirmed the existence of a Tc9 cell subset in both cultured system and in vivo (26). However, the role of this CD8 + T-cell subset has not been tested in cancer immunotherapy settings.…”

Human Vδ2 T cells are a major source of interleukin-9

“…The best characterized is the Th9 subset of CD4 T cells, but IL-9 production has also been found in CD8 T cells (29), innate lymphoid cells (30), and mast cells (31). So far, there is only one report of IL-9 production by γδ T cells in Schistosoma japonicum-infected mice (32).…”

Heterogeneity in the Differentiation and Function of CD8+ T Cells

“…T cells, a subpopulation of adaptive lymphocytes, play an important role in immunity to intracellular pathogens and tumors (Gattinoni et al 2012;Klenerman and Hill 2005;Kuang et al 2010;Lu et al 2014). They also contribute to the regulation of pathologic processes such as autoimmune and allergic disorders (Huber et al 2009;Kim and Cantor 2011;Loser et al 2010;Tang et al 2012;Visekruna et al 2013). Naïve CD8…”

“…However, they retained reduced IFN-c production revealing that their phenotype differed from Tc1 cells. Furthermore, increased frequencies of Tc9 cells were detected in the periphery of mice and humans with atopic dermatitis, a Th2-associated skin disease that often precedes asthma, suggesting that Tc9 cells contribute to propagation of Th2-mediated allergic inflammation (Visekruna et al 2013).…”

“…In a model of allergic airway disease, Tc9 cells acquire a Tc1/Tc2 hybrid phenotype characterized by simultaneous IL-13 and IFN-c production (Visekruna et al 2013), and in a melanoma model, Tc9 with IL-9 dependent anti-tumor reactivity transform to IFN-c and IL-2 producing Tc1 cells with a memory cell phenotype (Lu et al 2014).…”