IL-12 selectively programs effector pathways that are stably expressed in human CD8+ effector memory T cells in vivo

Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Blood (Impact Factor: 10.45). 08/2011; 118(14):3890-900. DOI: 10.1182/blood-2011-05-357111
Source: PubMed


CD8(+) cytotoxic T lymphocytes play a major role in defense against intracellular pathogens, and their functions are specified by antigen recognition and innate cytokines. IL-12 and IFN-α/β are potent "signal 3" cytokines that are involved in both effector and memory cell development. Although the majority of effector cells are eliminated as inflammation resolves, some survive within the pool of memory cells and retain immediate effector function. In this study, we demonstrate that IL-12 instructs a unique program of effector cell differentiation that is distinct from IFN-α/β. Moreover, effector memory (T(EM)) cells within peripheral blood display many common attributes of cells differentiated in vitro in response to IL-12, including proinflammatory cytokine secretion and lytic activity. A pattern of IL-12-induced genes was identified that demarcate T(EM) from central memory cells, and the ontologies of these genes correlated precisely with their effector functions. Further, we uncovered a unique program of gene expression that was acutely regulated by IL-12 and reflected in stable gene expression patterns within T(EM), but not T central memory cells in vivo. Thus, this study directly links a selective set of IL-12-induced genes to the programming of effector functions within the stable population of human CD8(+) T(EM) cells in vivo.

Download full-text


Available from: David Farrar
  • Source
    • "CD8+ cells were sorted by FACS based on chemokine receptors and were subjected to a redirected lysis assay as previously described [8]. Briefly, anti-CD3-coated THP-1 target cells were labeled by culturing in the presence of 150 μCi Na2[51Cr]O4 in complete growth media for 1.5 h. "
    [Show abstract] [Hide abstract]
    ABSTRACT: CD8+ cytotoxic T lymphocytes (CTLs) play a major role in defense against intracellular pathogens. During development, antigen-presenting cells secrete innate cytokines such as IL-12 and IFN-α, which drive CTL differentiation into diverse populations of effector and long-lived memory cells. Using whole transcriptome analyses, the serine/threonine protein kinase Tpl2/MAP3K8 was found to be induced by IL-12 and selectively expressed by effector memory (TEM) CTLs. Tpl2 regulates various inflammatory pathways by activating the ERK mediated MAP kinase pathway in innate immune cells such as macrophages and dendritic cells. In this study, we found that a specific small molecule Tpl2 inhibitor blocked IFN-γ and TNF-α secretion as well as cytolytic activity of human CTLs. This pathway was specific for human effector CTLs, as the Tpl2 inhibitor did not block IFN-γ and TNF-α secretion from murine effector CTLs. Further, IL-12 failed to induce expression of Tpl2 in murine CTLs, and Tpl2 deficient murine CTLs did not exhibit any functional deficiency either in vitro or in vivo in response to L. monocytogenes infection. In summary, we identified a species-specific role for Tpl2 in effector function of human CTLs, which plays a major role in adaptive immune responses to intracellular pathogens and tumors.
    Full-text · Article · Mar 2014 · PLoS ONE
  • Source
    • "Our findings support previous studies describing the aberrant activation state of peripheral blood SLE T cells [63]–[66]. We noted the robust expression of certain IFN-inducible transcripts in response to IFN-α stimulation [67]. DUSP5 expression was exclusively induced by IL-12. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by defective immune tolerance combined with immune cell hyperactivity resulting in the production of pathogenic autoantibodies. Previous gene expression studies employing whole blood or peripheral blood mononuclear cells (PBMC) have demonstrated that a majority of patients with active disease have increased expression of type I interferon (IFN) inducible transcripts known as the IFN signature. The goal of the current study was to assess the gene expression profiles of isolated leukocyte subsets obtained from SLE patients. Subsets including CD19(+) B lymphocytes, CD3(+)CD4(+) T lymphocytes and CD33(+) myeloid cells were simultaneously sorted from PBMC. The SLE transcriptomes were assessed for differentially expressed genes as compared to healthy controls. SLE CD33(+) myeloid cells exhibited the greatest number of differentially expressed genes at 208 transcripts, SLE B cells expressed 174 transcripts and SLE CD3(+)CD4(+) T cells expressed 92 transcripts. Only 4.4% (21) of the 474 total transcripts, many associated with the IFN signature, were shared by all three subsets. Transcriptional profiles translated into increased protein expression for CD38, CD63, CD107a and CD169. Moreover, these studies demonstrated that both SLE lymphoid and myeloid subsets expressed elevated transcripts for cytosolic RNA and DNA sensors and downstream effectors mediating IFN and cytokine production. Prolonged upregulation of nucleic acid sensing pathways could modulate immune effector functions and initiate or contribute to the systemic inflammation observed in SLE.
    Full-text · Article · Jun 2013 · PLoS ONE
  • Source
    Article: Got IELs?
    [Show abstract] [Hide abstract]
    ABSTRACT: Mucosal Immunology is the official publication of the Society of Mucosal Immunology (SMI). It aims to provide a forum for both basic and clinical scientists to discuss all aspects of immunity and inflammation involving mucosal tissues. The journal reflects the interests of scientists studying gastrointestinal, pulmonary, nasopharyngeal, oral, ocular, and genitourinary immunology through the publication of original research articles, scholarly reviews, and timely commentaries, editorials and letters.
    Preview · Article · Sep 2012 · Mucosal Immunology
Show more