Inflammatory IL-15 is required for optimal memory T cell responses

Richer, Martin J.; Pewe, Lecia; Hancox, Lisa S.; Hartwig, Stacey M.; Varga, Steven M.; Harty, John T.

doi:10.1172/jci81261

Cited by 91 publications

(87 citation statements)

References 47 publications

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“…Moreover, Richer et al . found that type I IFN is a major regulator of IL-15 expression in a PV (pichinde virus) infection mouse model26. In addition, in the current study, IL-15 was the possible cause of the increased NKp30 + NK cell frequency.…”

Section: Discussionsupporting

confidence: 52%

NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B

Shen

Liu

et al. 2016

Sci Rep

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A pressing need exists for improved therapeutic options for chronic hepatitis B (CHB). Pegylated-interferon-alpha (Peg-IFN-α) achieves sustained off-treatment responses in many cases because of its direct anti-viral effects and regulation of the immune response. However, non-responsiveness to Peg-IFN-α is frequent, and the mechanism is poorly understood. In this study, we found that the frequency and absolute number of NKp30+ natural killer (NK) cells increased markedly, accompanied by enhanced CD107a and IFN-γ production, during Peg-IFN-α-2b monotherapy or combination therapy with adefovir dipivoxil in patients with CHB, especially in responders. The responders and non-responders differed in the frequency of polyfunctional IFN-γ+ CD107+ NK cells. In addition, the increase in NKp30+ NK cells was negatively correlated with the HBV viral load and plasma HBeAg. Moreover, it was found that IL-15 may contribute to the up-regulation of NKp30 on the NK cells, and this up-regulation was not induced in vitro by Peg-IFN-α-2b alone. However, in the non-responders, these NKp30+ NK cells were dysfunctional because of increased NKG2A expression, which partly explains the inactivation of NKp30+ NK cells and the reduced capacity of these cells to produce antiviral cytokines. These findings may provide a new mechanism to explain the variable efficacy of Peg-IFN-α-2b therapy.

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Section: Discussionsupporting

confidence: 52%

NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B

Shen

Liu

et al. 2016

Sci Rep

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“…IL-15 is often described as a homeostatic cytokine that is important for the long-term maintenance of memory CD8 + T cell populations, but also functions to stimulate effector functions of T cells (25, 26). To investigate whether steady-state exposure to IL-15 maintained the synthesis of selectin ligands on memory CD8 + T cells, we utilized an IL-15 neutralizing antibody (27).…”

Section: Resultsmentioning

confidence: 99%

Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8 ⁺ T cells

et al. 2017

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Trafficking of memory CD8+ T cells out of the circulation is essential to provide protective immunity against intracellular pathogens in non-lymphoid tissues. However, the molecular mechanisms that dictate the trafficking potential of diverse memory CD8+ T cell populations are not completely defined. Here, we show that following infection or inflammatory challenge, central memory (TCM) CD8+ T cells rapidly traffic into non-lymphoid tissues, whereas most effector memory (TEM) cells remain in the circulation. Furthermore, we demonstrate that cellular migration of memory CD8+ T cells into non-lymphoid tissues is driven by IL-15-stimulated enzymatic synthesis of core 2 O-glycans, which generates functional ligands for E- and P-selectin. Given that IL-15 stimulated expression of glycosyltransferase enzymes is largely a feature of TCM CD8+ T cells, this allows TCM to selectively migrate out of the circulation and into non-lymphoid tissues. Thus, these data show that the capacity to synthesize core 2 O-glycans identifies the memory CD8+ T cells with tissue-trafficking potential and that TCM, and not TEM, is the major subset that enters non-lymphoid tissues following infection or tissue injury.

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“…The memory CD8 + T cells produced IFNγ overall promoted further recruitment and activation of multiple innate immune effector cells by enhancing secretion of chemokines (CCL2, CXCL1, CXCL10 and others) and IFNγ signaling to innate myeloid and lymphoid cells [22–24]. Sensing of cytokinic signals was also proposed to allow for cell-intrinsic “pre-activation” of host memory CD8 + T cells, making them “ready to go”, e.g., to initiate proliferation and possibly other functions upon further cognate antigen encounter [17, 25]. …”

Section: Memory Cd8+ T Cells Can Act As Potent “Innate-like” Sensors mentioning

confidence: 99%

“…Despite evidence that NKG2D + memory CD8 + T cells may contribute to lysis of damaged/stressed RAE1ε + cells [57], antigen-independent activation, that include adhesion, recruitment and initial effector differentiation, most likely contribute to an early “innate-like” protective reponse that make the antigen-dependent memory response “fitter, faster and better” [17, 25]. Without cognate antigen, memory CD8 + T cells can initiate T cell proliferation [18, 21, 25], but the extent of their expansion remains limited and antigen is necessary to achieve full T cell expansion [17, 34, 37, 49]. In the initial hours following memory T cell reactivation and prior to T cell robust expansion, cognate antigen triggering allows both systemic (SLO) and tissue-resident (skin) memory CD8 + T cells to arrest and establish stable interactions with virus-infected cells [44, 52].…”

Section: Memory Cd8+ T Cells Can Act As Potent “Innate-like” Sensors mentioning

confidence: 99%

Memory CD8 + T Cells: Innate-Like Sensors and Orchestrators of Protection

Lauvau

Boutet

Williams

et al. 2016

Trends in Immunology

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Recent findings have revealed roles for systemic and mucosal-resident memory CD8+ T cells in the orchestration of innate immune responses critical to host defense upon microbial infection. Here we integrate these findings into the current understanding of the molecular and cellular signals controlling memory CD8+ T cell reactivation, and the mechanisms by which these cells mediate effective protection in vivo. The picture that emerges presents memory CD8+ T cells as early sensors of danger signals, mediating protective immunity both through licensing of cellular effectors of the innate immune system and via the canonical functions associated with memory T cells. We discuss implications to the development of T cell vaccines and therapies, and highlight important areas in need of further investigation.

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Inflammatory IL-15 is required for optimal memory T cell responses

Cited by 91 publications

References 47 publications

NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B

NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B

Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8 ⁺ T cells

Memory CD8 + T Cells: Innate-Like Sensors and Orchestrators of Protection

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Inflammatory IL-15 is required for optimal memory T cell responses

Cited by 91 publications

References 47 publications

NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B

NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B

Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8 + T cells

Memory CD8 + T Cells: Innate-Like Sensors and Orchestrators of Protection

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Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8 ⁺ T cells