Dual Roles of IL-15 in Maintaining IL-7RαlowCCR7− Memory CD8+ T Cells in Humans via Recovering the Phosphatidylinositol 3-Kinase/AKT Pathway

Kim, Hang Rae; Hwang, Kyung‐A; Kang, Insoo

doi:10.4049/jimmunol.179.10.6734

Cited by 28 publications

(26 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, adding anti-IL-2 antibodies substantially decreased their proliferation ( Figure 2D). In accordance with the finding of our previous study (6), IL-7Ra low EM CD8 1 T cells had impaired cell proliferation in response to anti-CD3/CD28 stimulation. Also, the survival capacity of activated IL-6Ra high EM CD8…”

Section: Identification Of An Em Cd8supporting

confidence: 81%

“…Indeed, EM CD8 1 T cells in human peripheral blood contain two subsets with high and low levels of IL-7Ra expression (IL-7Ra high and -7Ra low ) (5). The two cell subsets have distinct characteristics with respect to cell survival and proliferation (5,6), suggesting a role for cytokine receptors like IL-7Ra in identifying different subsets of EM CD8 1 T cell.…”

Section: Memory Cd8mentioning

confidence: 99%

See 1 more Smart Citation

IL-6 Receptor α Defines Effector Memory CD8⁺T Cells Producing Th2 Cytokines and Expanding in Asthma

Lee¹,

You

Shin³

et al. 2014

Am J Respir Crit Care Med

Self Cite

View full text Add to dashboard Cite

Rationale: Cytokine receptors can be markers defining different T-cell subsets and considered as therapeutic targets. The association of IL-6 and IL-6 receptor a (IL-6Ra) with asthma was reported, suggesting their involvement in asthma.Objectives: To determine whether and how IL-6Ra defines a distinct effector memory (EM) CD81 T-cell population in health and disease. Methods: EM CD81 T cells expressing IL-6Ra (IL-6Ra high ) were identified in human peripheral blood and analyzed for function, gene, and transcription factor expression. The relationship of these cells with asthma was determined using blood and sputum.Measurements and Main Results: A unique population of IL-6Ra high EM CD8 1 T cells was found in peripheral blood. These cells that potently proliferated, survived, and produced high levels of the Th2-type cytokines IL-5 and IL-13 had increased levels of GATA3 and decreased levels of T-bet and Blimp-1 in comparison with other EM CD8 1 T cells. In fact, GATA3 was required for IL-6Ra expression. Patients with asthma had an increased frequency of IL-6Ra high EM CD81 T cells in peripheral blood compared with healthy control subjects. Also, IL-6Ra high EM CD8 1 T cells exclusively produced IL-5 and IL-13 in response to asthma-associated respiratory syncytial virus and bacterial superantigens.Conclusions: Human IL-6Ra high EM CD8 1 T cells is a unique cell subset that may serve as a reservoir for effector CD8 1 T cells, particularly the ones producing Th2-type cytokines, and expand in asthma.

show abstract

Section: Identification Of An Em Cd8supporting

confidence: 81%

Section: Memory Cd8mentioning

confidence: 99%

IL-6 Receptor α Defines Effector Memory CD8⁺T Cells Producing Th2 Cytokines and Expanding in Asthma

Lee¹,

You

Shin³

et al. 2014

Am J Respir Crit Care Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…The reduced proliferative capacity in the KLRG1 hi CD27 lo IL-7Rα lo cells has been attributed to increased expression of the cell cycle inhibitor p27 kip and decreased expression of BMI1 relative to the IL-7Rα hi subset (17,36). In addition, the terminally differentiated KLRG1 hi CD27 lo IL-7Rα lo T cells show poor AKT activation in response to both cytokine and TCR stimulation (21,37,38). Given that AKT activity is necessary for cell survival in a variety of cell types, we hypothesized that the reduced AKT activity in KLRG1 hi IL-7Rα lo terminal effector cells was the basis of their shortened lifespan (39).…”

Section: Discussionmentioning

confidence: 99%

“…KLRG1 lo IL-7Rα hi MPECs give rise to both T EM and T CM populations, whereas the fraction of terminally differentiated KLRG1 hi IL-7R lo cells that persists into the memory stage is overwhelmingly composed of CD62L lo T EM cells (10,13,47). However, terminally differentiated T EM (KLRG1 hi CD27 lo CD62L lo ) display impaired AKT phosphorylation compared with their KLRG1 lo CD27 hi counterparts, which suggests that an additional AKT-independent mechanism for CD62L repression exists in CD8 T cells (21,37). We would postulate that PI3K/AKTdependent regulation of CD62L expression predominantly occurs in the T CM subset, which has increased AKT signaling.…”

Section: Discussionmentioning

confidence: 99%

“…For secondary infection, C57BL/6 mice containing ∼2,500 P14 CD8 T cells were infected with 2 × 10 4 cfu recombinant Listeria monocytogenes i.v. that expresses the LCMV GP [33][34][35][36][37][38][39][40][41] epitope (strain XFL203, but referred to as Listeria-GP33) (3). All experiments were done with approved Institutional Animal Care and Use Committee protocols.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival

Hand

Cui²,

Jung³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

194

191

View full text Add to dashboard Cite

During viral infection, effector CD8 T cells contract to form a population of protective memory cells that is maintained by IL-7 and IL-15. The mechanisms that control effector cell death during infection are poorly understood. We investigated how short-and long-lived antiviral CD8 T cells differentially used the survival and cell growth pathways PI3K/AKT and JAK/STAT5. In response to IL-15, long-lived memory precursor cells activated AKT significantly better than shortlived effector cells. However, constitutive AKT activation did not enhance memory CD8 T-cell survival but rather repressed IL-7 and IL-15 receptor expression, STAT5 phosphorylation, and BCL2 expression. Conversely, constitutive STAT5 activation profoundly enhanced effector and memory CD8 T-cell survival and augmented homeostatic proliferation, AKT activation, and BCL2 expression. Taken together, these data illustrate that effector and memory cell viability depends on properly balanced PI3K/AKT signaling and the maintenance of STAT5 signaling.apoptosis | cytokine signaling | interleukin 15 | interleukin 7 | lymphocytic choriomeningitis virus M emory CD8 T cells form from a much larger effector population and provide long-term immunity against subsequent infections via rapid reactivation. The exact biochemical mechanism governing the survival of memory cells and apoptosis of the majority of effector cells is not well understood (1). As naïve T cells differentiate into effector and memory T cells, cytokines play a key role in their differentiation and survival. IL-2, IL-7, and IL-15 promote the expansion and survival of activated T cells (2). As memory CD8 T cells form following acute viral infection, two of these cytokines, IL-15 and IL-7, direct memory T cell survival and homeostasis (3, 4). Downstream of their specific receptors, IL-7 and IL-15 activate two primary pathways: janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) and phosphoinositide 3-kinase (PI3K)/AK-transforming (AKT). Activation of these two pathways results in decreased levels of proapoptotic proteins, increased expression of antiapoptotic genes such as BCL2, and activation of cellular growth and proliferation pathways regulated by mTOR and cyclins (5). The balance between these pro-and antiapoptotic factors controls the survival of CD8 T cells after immunization (6).Early models predicted that effector CD8 T-cell contraction was a result of deprivation of T-cell growth factor cytokines that wane during the later stages of infection and that survival was determined via the stochastic interaction of effector T cells with these cytokines. However, effector CD8 T cells are a heterogeneous population composed of cells with varying intrinsic potential for survival and differentiation into memory cells (3,7,8). During several types of infections [such as lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), Listeria monocytogenes, and Toxoplasma gondii], most of the effector CD8 T cells terminally differentiate and become short-lived, but ...

show abstract

Characterization of Effector Memory CD8+ T Cells in the Synovial Fluid of Rheumatoid Arthritis

et al. 2012

Self Cite

View full text Add to dashboard Cite

Little is known about the cellular characteristics of CD8(+) T cells in rheumatoid arthritis (RA). We addressed this by investigating whether the frequency of the CD8(+) T cell subsets and their phenotypic characteristics are altered in the peripheral blood and synovial fluid (SF) from patients with RA. In this study, CD8(+) T cells, mainly CD45RA(-) effector memory (EM) CD8(+) T cells, were increased significantly in the SF, but not in the peripheral blood from RA patients, compared with healthy controls. The synovial EM CD8(+) T cells were activated phenotypes with high levels of CD80, CD86, and PD-1, and had a proliferating signature in vivo upon Ki-67 staining, whereas the Fas-positive cells were prone to apoptosis. In addition, EM CD8(+) T cells in the SF were less cytotoxic, as they expressed less perforin and granzyme B. In particular, the proportions of synovial fluid mononuclear cells that were CCR4(+)CD8(+) T cells and IL-4-producing CD8(+) T cells (i.e., Tc2 cells) were significantly higher than those in peripheral blood mononuclear cells of patients with RA and healthy controls. In addition, the number of IL-10-producing CD8(+) suppressor T (Ts) cells increased significantly in the SF of RA patients. Especially, CD8(+) T cells were inversely correlated with disease activity. These findings strongly suggest that EM CD8(+) T cells in the SF are increased, likely because of inflammation, and they may be involved in modulating inflammation, thereby affecting the development and progression of RA.

show abstract

Dual Roles of IL-15 in Maintaining IL-7RαlowCCR7− Memory CD8+ T Cells in Humans via Recovering the Phosphatidylinositol 3-Kinase/AKT Pathway

Cited by 28 publications

References 37 publications

IL-6 Receptor α Defines Effector Memory CD8⁺T Cells Producing Th2 Cytokines and Expanding in Asthma

IL-6 Receptor α Defines Effector Memory CD8⁺T Cells Producing Th2 Cytokines and Expanding in Asthma

Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival

Characterization of Effector Memory CD8+ T Cells in the Synovial Fluid of Rheumatoid Arthritis

Contact Info

Product

Resources

About

Dual Roles of IL-15 in Maintaining IL-7RαlowCCR7− Memory CD8+ T Cells in Humans via Recovering the Phosphatidylinositol 3-Kinase/AKT Pathway

Cited by 28 publications

References 37 publications

IL-6 Receptor α Defines Effector Memory CD8+T Cells Producing Th2 Cytokines and Expanding in Asthma

IL-6 Receptor α Defines Effector Memory CD8+T Cells Producing Th2 Cytokines and Expanding in Asthma

Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival

Characterization of Effector Memory CD8+ T Cells in the Synovial Fluid of Rheumatoid Arthritis

Contact Info

Product

Resources

About

IL-6 Receptor α Defines Effector Memory CD8⁺T Cells Producing Th2 Cytokines and Expanding in Asthma

IL-6 Receptor α Defines Effector Memory CD8⁺T Cells Producing Th2 Cytokines and Expanding in Asthma