The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8+ T cells.

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. monocytogenes-specific 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.

IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis.

IL-17-producing CD8+ T (Tc17) cells are detectible in multiple sclerosis (MS) lesions; however, their contribution to the disease is unknown. To identify functions of Tc17 cells, we induced EAE, a murine model of MS, in mice lacking IFN regulatory factor 4 (IRF4). IRF4-deficient mice failed to generate Tc17 and Th17 cells and were resistant to EAE. After adoptive transfer of WT CD8+ T cells and subsequent immunization for EAE induction in these mice, the CD8+ T cells developed a Tc17 phenotype in the periphery but could not infiltrate the CNS. Similarly, transfer of small numbers of WT CD4+ T cells alone did not evoke EAE, but when transferred together with CD8+ T cells, IL-17-producing CD4+ (Th17) T cells accumulated in the CNS and mice developed severe disease. Th17 accumulation and development of EAE required IL-17A production by CD8+ T cells, suggesting that Tc17 cells are required to promote CD4+ T cell-mediated induction of EAE. Accordingly, patients with early-stage MS harbored a greater number of Tc17 cells in the cerebrospinal fluid than in peripheral blood. Our results reveal that Tc17 cells contribute to the initiation of CNS autoimmunity in mice and humans by supporting Th17 cell pathogenicity.

Tc9 cells, a new subset of CD8(+) T cells, support Th2-mediated airway inflammation.

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-ß 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.