Cytokines are critical determinants for specification of lineage-defining transcription factors of CD4+ T cell subsets. Little is known, however, about how cytokines regulate expression of T-bet and eomesodermin (Eomes) in effector and memory CD8+ T cells. We now report that IL-12, a signature of cell-mediated immunity, represses Eomes while positively regulating T-bet in effector CD8+ T cells during infection with Listeria monocytogenes. After resolution of infection and abatement of IL-12 signaling, Eomes expression rises whereas T-bet expression declines in memory CD8+ T cells. Eomes becomes derepressed in effector cells by ablation of IL-12 signaling. In the absence of IL-12, the dynamics of clonal expansion and contraction are also perturbed. Together, these results reveal how a pathogen-associated signal, such as IL-12, could act as a switch, regulating appropriate clonal growth and decline while, in parallel, shaping a unique pattern of fate-determining transcription factors.
"T-bet is known to modulate a number of genes involved in T-cell mobilization (CXCR3), cell signaling (IL12Rβ1), and cytolytic signaling molecules (IFNγ) (8). Additionally, high levels of T-bet expression are closely associated with cytotoxic CD8+ T-cell effector differentiation and function, including the upregulation of perforin and granzyme B in antigen-specific cells (9–12). T-bet has been implicated in sustaining memory subsets (13–16), however, T-bet levels decline as cells become more memory-like (17). "
[Show abstract][Hide abstract] ABSTRACT: The T-box transcription factors T-bet and Eomesodermin (Eomes) have been well defined as key drivers of immune cell development and cytolytic function. While the majority of studies have defined the roles of these factors in the context of murine T-cells, recent results have revealed that T-bet, and possibly Eomes, are expressed in other immune cell subsets. To date, the expression patterns of these factors in subsets of human peripheral blood mononuclear cells beyond T-cells remain relatively uncharacterized. In this study, we used multiparametric flow cytometry to characterize T-bet and Eomes expression in major human blood cell subsets, including total CD4(+) and CD8(+) T-cells, γδ T-cells, invariant NKT cells, natural killer cells, B-cells, and dendritic cells. Our studies identified novel cell subsets that express T-bet and Eomes and raise implications for their possible functions in the context of other human immune cell subsets besides their well-known roles in T-cells.
Frontiers in Immunology 05/2014; 5:217. DOI:10.3389/fimmu.2014.00217
"Prolonged IL-2 signaling promotes the development of terminally differentiated short-lived effector cells (SLECs, typically marked by CD127 lo KLRG1 hi ), at the expense of effector cells possessing self-renewal potential (also known as MPECs [memory precursor effector cells], CD127 hi KLRG1 lo ). In addition to IL-2R signaling, inflammatory signals (i.e., IL-12 and type I interferon) promote expression of T-bet and repression of Eomes in the responding CD8 + T cells, resulting in differentiation toward SLEC phenotypes (Curtsinger et al., 2003; Joshi et al., 2007; Takemoto et al., 2006), although it is not known to the extent this process is dependent on IL-2-IL-2R signaling. Similarly, elevated Blimp-1 expression in CD8 + T cells receiving sustained survival signals (i.e., marked by elevated CD25 expression) favors the generation of SLECs by reducing Bcl-6 expression, which in turn represses the acquisition of the MPEC phenotype by the responding CD8 + T cells (Crotty et al., 2010; Kallies et al., 2009; Rutishauser et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: The contribution of different DC subsets to effector and memory CD8(+) T cell generation during infection and the mechanism by which DCs controls these fate decisions is unclear. Here we demonstrated that the CD103(+) and CD11b(hi) migratory respiratory DC (RDC) subsets after influenza virus infection activated naive virus-specific CD8(+) T cells differentially. CD103(+) RDCs supported the generation of CD8(+) T effector (Teff) cells, which migrate from lymph nodes to the infected lungs. In contrast, migrant CD11b(hi) RDCs activated CD8(+) T cells characteristic of central memory CD8(+) T (CD8(+) Tcm) cells including retention within the draining lymph nodes. CD103(+) RDCs expressed CD24 at an elevated level, contributing to the propensity of this DC subpopulation to support CD8(+) Teff cell differentiation. Mechanistically, CD24 was shown to regulate CD8(+) T cell activation through HMGB1-mediated engagement of T cell RAGE. Thus, there is distribution of labor among DC subsets in regulating CD8(+) T cell differentiation.
"For instance, activation of CD8+ cells also primarily depends on glycolysis , and differentiation of effector CD8+ cells requires mTORC1-dependent T-bet expression . Most critically, mTOR is involved in the transition of effector to memory CD8+ T cells (Figure 2), and this appears to rely on conversion of T-bet to eomesodermin transcription factor expression [24-26]; blocking mTOR with rapamycin has this exact effect, and therefore promotes the development and sustenance of memory T cells that transition efficiently into effector cells highly capable of producing immune responses to, for instance, tumours . Similar to Treg cells, memory CD8+ T cells depend on mitochondrial oxidative phosphorylation for energy (rather than glycolysis) and are driven by STAT5 signalling. "
[Show abstract][Hide abstract] ABSTRACT: The known role of mammalian target of rapamycin (mTOR) in the immune response has been rapidly evolving, from what was once thought to be a simple immunosuppressive antiproliferative effect on T cells to a very complex central role that serves to integrate multiple signals given to T cells, B cells and antigen-presenting cells. The complexity of this topic is demonstrated by recent data suggesting that mTOR inhibition can either inhibit or promote certain aspects of immune responses, depending on the nature of the antigenic stimulus, and the environmental conditions cueing the cellular immunological players. There is even evidence that, under mTOR inhibition, an immune response to one foreign entity (for example, an organ transplant) may be simultaneously completely different to that of another (for example, tumour or microorganism). To understand how this might be possible, it is necessary to investigate the central role that mTOR seems to have in shaping the immune response. This review is aimed at examining how mTOR controls the development and function of key immune cells, and puts this information primarily in the context of organ transplant rejection and post-transplant malignancy.
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