Reciprocal responsiveness to interleukin-12 and interferon-α specifies human CD8+ effector versus central memory T-cell fates

Ramos, Hilario J.; Davis, Ann M.; Cole, Alexander; Schatzle, John D.; Forman, James; Farrar, J. David

doi:10.1182/blood-2008-11-188458

Cited by 60 publications

(70 citation statements)

References 46 publications

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“…We and others have shown that IL-12 and IFN-a also act directly on human naive CD8 T cells promoting the proliferation whereas favoring the acquisition of effector functions (25,26). However, there is scant information about the effects of innate inflammatory cytokines on the differentiation of human naive CD8 T cells into effector or memory CTLs.…”

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confidence: 99%

“…However, there is scant information about the effects of innate inflammatory cytokines on the differentiation of human naive CD8 T cells into effector or memory CTLs. Previous data from Farrar's group suggest that IL-12 and IFN-a behave as nonredundant signals that differentially regulate the development of memory CTLs with T effector memory cell (TEM; CD62L low CCR7l ow ) or T central memory cell (TCM; CD62L hi CCR7 hi ) phenotypes, respectively (25). Frequently, specific surface markers have been used to ascribe functional attributes to memory CTLs, but phenotype cannot be directly translated into functional properties (27).…”

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confidence: 99%

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CD8 T Cell Priming in the Presence of IFN-α Renders CTLs with Improved Responsiveness to Homeostatic Cytokines and Recall Antigens: Important Traits for Adoptive T Cell Therapy

Hervás-Stubbs

Mancheño

Riezu-Boj

et al. 2012

The Journal of Immunology

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Previous mouse and human studies have demonstrated that direct IFN-α/β signaling on naive CD8 T cells is critical to support their expansion and acquisition of effector functions. In this study, we show that human naive CD8 T cells primed in the presence of IFN-α possess a heightened ability to respond to homeostatic cytokines and to secondary Ag stimulation, but rather than differentiating to effector or memory CTLs, they preserve nature-like phenotypic features. These are qualities associated with greater efficacy in adoptive immunotherapy. In a mouse model of adoptive transfer, CD8 T cells primed in the presence of IFN-α are able to persist and to mediate a robust recall response even after a long period of naturally driven homeostatic maintenance. The long-lasting persistence of IFN-α–primed CD8 T cells is favored by their enhanced responsiveness to IL-15 and IL-7, as demonstrated in IL-15−/− and IL-7−/− recipient mice. In humans, exposure to IFN-α during in vitro priming of naive HLA-A2+ CD8 T cells with autologous dendritic cells loaded with MART126–35 peptide renders CD8 T cells with an improved capacity to respond to homeostatic cytokines and to specifically lyse MART1-expressing melanoma cells. Furthermore, in a mouse model of melanoma, adoptive transfer of tumor-specific CD8 T cells primed ex vivo in the presence of IFN-α exhibits an improved ability to contain tumor progression. Therefore, exposure to IFN-α during priming of naive CD8 T cells imprints decisive information on the expanded cells that can be exploited to improve the efficacy of adoptive T cell therapy.

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CD8 T Cell Priming in the Presence of IFN-α Renders CTLs with Improved Responsiveness to Homeostatic Cytokines and Recall Antigens: Important Traits for Adoptive T Cell Therapy

Hervás-Stubbs

Mancheño

Riezu-Boj

et al. 2012

The Journal of Immunology

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“…Further, in human, both Eomes and T-bet are regulated by IL-12 in CD8 ϩ and CD4 ϩ T cells, respectively. 18,26,37 As such, it is unclear how the IL-12 signaling pathway regulates only one of the 2 transcription factors in each cell type and whether species differences can account for this regulation.In addition to Eomes, this analysis revealed 4 additional unique IL-12-induced intracellular regulators that were expressed in T EM in vivo. First, we identified both a dual-specificity phosphatase (DUSP5) and a MAP kinase (MAP3K8), both of which have been implicated in directly regulating effector T-cell activity.…”

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confidence: 99%

“…5,19 Our previous studies defined unique roles for IL-12 and IFN-␣/␤ in regulating effector and memory functions in both human CD4 ϩ and CD8 ϩ T cells. 18,26 Although IL-12 was unique in its ability to regulate effector cell commitment, the downstream targets of IL-12 that mediate this activity have not been elucidated. In the current study, we used a hypothesis-driven approach to dissect IL-12-driven gene expression pathways governing human CD8 ϩ T effector cell development.…”

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confidence: 99%

“…Thus, the differential induction of IL-12-regulated genes within the actively dividing population correlated precisely with increased sensitivity to IL-12 and acquisition of effector function observed in Figure 1 and in previous studies. 18 In mice, both IL-12 and IFN-␣ can promote effector CTL development, albeit IL-12 being more potent in this activity than IFN-␣. 16 Agarwal et al have further demonstrated that these cytokine signaling pathways regulate an overlapping spectrum of effector response genes, such as IFN-␥ and granzyme B, suggesting some level of redundancy between these signals in mice.…”

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

Chowdhury¹,

Ramos²,

Davis³

et al. 2011

Blood

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IntroductionThe pool of circulating CD8 ϩ cytotoxic T lymphocytes (CTLs) is remarkably heterogeneous, consisting of antigen inexperienced naive cells as well as multiple populations of effector and memory subsets. 1 Various models have been proposed to explain the genesis of memory subsets, and a significant body of evidence suggests that long-lived memory cells are derived from early effector cells that survive contraction as antigen loads wane. 2 If so, then the diverse spectrum of memory cells that fall into either effector memory (T EM ) or central memory (T CM ) categories would also be predicted to be derived from a common pool of primary effectors. 3 Regardless of their origins, T EM and T CM differ substantially in their functional capabilities, and the extrinsic signals that regulate their development are complex and multifactorial. Among these factors, innate cytokines are key signals that regulate effector cell differentiation, 4 with IL-12 and type I interferon (IFN-␣/␤) playing important roles in both effector and memory cell development. 5 In humans, CD8 ϩ subsets have been distinguished based on their differential expression of various markers, including CD45RA, CD27, CD28, CCR7, CD62L, CD127, and CXCR3. [6][7][8][9] Based solely on the expression of CCR7 and CD45RA, early studies defined 4 main subsets: naive (CD45RA ϩ /CCR7 ϩ ), T CM (CD45RA Ϫ / CCR7 ϩ ), T EM (CD45RA Ϫ /CCR7 Ϫ ), and effector memory-RA (T EMRA , CD45RA ϩ /CCR7 Ϫ ). 10 Aside from their differential expression of CD45RA and other cell surface markers, T EM uniformly exhibit rapid effector functions in response to antigen activation. Further, T EM do not generally require CD28-mediated costimulation or innate cytokines to secrete proinflammatory cytokines or to lyse target cells. 11,12 Thus, if T EM cells are direct descendants of effector CTLs, then the maintenance of effector functions within T EM would suggest early programming during the priming phase of infection.In mice, both IL-12 and IFN-␣/␤ exert somewhat overlapping and redundant effects by driving effector cell development. 5,[13][14][15][16][17] Although IL-12 seems to be more potent at promoting IFN-␥ secretion, both IL-12 and IFN-␣/␤ are equally effective at regulating lytic activity in murine CD8 ϩ T cells. In contrast, IL-12 and IFN-␣/␤ appear to play very distinct roles in priming human CD8 ϩ T-cell responses. Recently, Ramos et al demonstrated a preferential role for IL-12 over IFN-␣/␤ in driving cytokine expression and lytic activity in human CTLs. 18 Conversely, IFN-␣/␤ enhanced the development of a subpopulation of cells that displayed phenotypic and functional characteristics of T CM . Programming of effectors by IL-12 was accompanied by progression of cells through cell division and was altered by the strength of TCR engagement. IL-12 programmed effector cell development, which was regulated by induction of the IL-12 receptor at each division as cells proliferated in response to TCR activation. In contrast, IFN-␣/␤ tended to slow the progression of cell divi...

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Effects of IFN‐α as a signal‐3 cytokine on human naïve and antigen‐experienced CD8⁺ T cells

et al. 2010

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IFN-α/β link innate and adaptive immune responses by directly acting on naïve CD8(+) T cells. This concept unveiled in mice remains unexplored in humans. To investigate that, human CD8(+) CD45RO(-) cells were stimulated with beads coated with anti-CD3 and anti-CD28 mAb, mimicking Ag (type-1) and co-stimulatory (type-2) signals, in the presence or absence of IFN-α and their transcriptional profiles were defined by cDNA-microarrays. We show that IFN-α provides a strong third signal directly to human CD8(+) T cells resulting in regulation of critical genes for their overall activation. This transcriptional effect was substantiated at the protein level and verified by functional assays. Interestingly, the biological effects derived from this stimulation vary depending on the CD8(+) T-cell population. Thus, whereas IFN-α increases the proliferative capacity of naïve CD8(+) T cells, it inhibits or does not affect the proliferation of Ag-experienced cells, such as memory and effector CTL, including CMV-specific lymphocytes. Cytolysis and IFN-γ-secretion of all these populations are enhanced by IFN-α-derived signals, which are critical in naïve CD8(+) T cells for acquisition of effector functions. Our findings in human CD8(+) T cells are informative to understand and improve IFN-α-based therapies for viral and malignant diseases.

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Reciprocal responsiveness to interleukin-12 and interferon-α specifies human CD8+ effector versus central memory T-cell fates

Cited by 60 publications

References 46 publications

CD8 T Cell Priming in the Presence of IFN-α Renders CTLs with Improved Responsiveness to Homeostatic Cytokines and Recall Antigens: Important Traits for Adoptive T Cell Therapy

CD8 T Cell Priming in the Presence of IFN-α Renders CTLs with Improved Responsiveness to Homeostatic Cytokines and Recall Antigens: Important Traits for Adoptive T Cell Therapy

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

Effects of IFN‐α as a signal‐3 cytokine on human naïve and antigen‐experienced CD8⁺ T cells

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Reciprocal responsiveness to interleukin-12 and interferon-α specifies human CD8+ effector versus central memory T-cell fates

Cited by 60 publications

References 46 publications

CD8 T Cell Priming in the Presence of IFN-α Renders CTLs with Improved Responsiveness to Homeostatic Cytokines and Recall Antigens: Important Traits for Adoptive T Cell Therapy

CD8 T Cell Priming in the Presence of IFN-α Renders CTLs with Improved Responsiveness to Homeostatic Cytokines and Recall Antigens: Important Traits for Adoptive T Cell Therapy

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

Effects of IFN‐α as a signal‐3 cytokine on human naïve and antigen‐experienced CD8+ T cells

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Effects of IFN‐α as a signal‐3 cytokine on human naïve and antigen‐experienced CD8⁺ T cells