Robust cytotoxic CD8 + T-cell response is important for immunity to intracellular pathogens. Here, we show that the transcription factor IFN Regulatory Factor 4 (IRF4) is crucial for the protective CD8 + T-cell response to the intracellular bacterium Listeria monocytogenes. IRF4-deficient (Irf4 −/− ) mice could not clear L. monocytogenes infection and generated decreased numbers of L. monocytogenesspecific CD8 + T cells with impaired effector phenotype and function. Transfer of wild-type CD8 + T cells into Irf4 −/− mice improved bacterial clearance, suggesting an intrinsic defect of CD8 + T cells in Irf4 −/− mice. Following transfer into wild-type recipients, Irf4 −/− CD8 + T cells became activated and showed initial proliferation upon L. monocytogenes infection. However, these cells could not sustain proliferation, produced reduced amounts of IFN-γ and TNF-α, and failed to acquire cytotoxic function. Forced IRF4 expression in Irf4 −/− CD8 + T cells rescued the defect. During acute infection, Irf4 −/− CD8 + T cells demonstrated diminished expression of B lymphocyte-induced maturation protein-1 (Blimp-1), inhibitor of DNA binding (Id)2, and T-box expressed in T cells (T-bet), transcription factors programming effector-cell generation. IRF4 was essential for expression of Blimp-1, suggesting that altered regulation of Blimp-1 contributes to the defects of Irf4 −/− CD8 + T cells. Despite increased levels of B-cell lymphoma 6 (BCL-6), Eomesodermin, and Id3, Irf4 −/− CD8 + T cells showed impaired memory-cell formation, indicating additional functions for IRF4 in this process. As IRF4 governs B-cell and CD4 + T-cell differentiation, the identification of its decisive role in peripheral CD8 + T-cell differentiation, suggests a common regulatory function for IRF4 in adaptive lymphocytes fate decision.
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 ...
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