2016
DOI: 10.1038/nature19330
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Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy

Abstract: Chronic viral infections are characterized by a state of CD8+ T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor1–4. A better understanding of the mechanisms that regulate CD8+ T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8+ T cells. Here we identify a population of virus-specific CD8+ T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically inf… Show more

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Cited by 1,432 publications
(1,879 citation statements)
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References 37 publications
(48 reference statements)
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“…In particular, T cells isolated from patients treated with vaccination alone showed a less differentiated phenotype in terms of CD28 expression (Arm1, mean ± SD 56% ± 27%), as compared with cells isolated from patients treated with chemo-immunotherapy (Arm2, mean ± SD 6% ± 10%; P < 0.0001). The intermediate differentiated profile of gp100 + T-cell clonotypes derived from vaccination alone was also supported by the expression analysis of C-X-C chemokine receptor type 5 (CXCR5), a marker recently associated with memory stem cell-like CD8 + T cells, 26 , 27 significantly higher in Arm1 (mean ± SD 43% ± 6.9%) as compared with Arm2 (mean ± SD 34% ± 3.3%, P = 0.03), either alone (Table 1) or in co-expression with CD28 ( P = 0.006, data not shown). The analysis of the expression of CD56 and Natural Killer Group 2D (NKG2D), markers for activation and effector functionality, revealed no difference for CD56 but a heterogeneous expression for NKG2D (Table 1).…”
Section: Resultsmentioning
confidence: 76%
See 1 more Smart Citation
“…In particular, T cells isolated from patients treated with vaccination alone showed a less differentiated phenotype in terms of CD28 expression (Arm1, mean ± SD 56% ± 27%), as compared with cells isolated from patients treated with chemo-immunotherapy (Arm2, mean ± SD 6% ± 10%; P < 0.0001). The intermediate differentiated profile of gp100 + T-cell clonotypes derived from vaccination alone was also supported by the expression analysis of C-X-C chemokine receptor type 5 (CXCR5), a marker recently associated with memory stem cell-like CD8 + T cells, 26 , 27 significantly higher in Arm1 (mean ± SD 43% ± 6.9%) as compared with Arm2 (mean ± SD 34% ± 3.3%, P = 0.03), either alone (Table 1) or in co-expression with CD28 ( P = 0.006, data not shown). The analysis of the expression of CD56 and Natural Killer Group 2D (NKG2D), markers for activation and effector functionality, revealed no difference for CD56 but a heterogeneous expression for NKG2D (Table 1).…”
Section: Resultsmentioning
confidence: 76%
“…This early differentiated effector memory CD8 + CD28 high PD1 + CXCR5 + subgroup has recently been reported as the only proliferative subset after anti-PD-1 blockade in mice chronically infected with a Lymphocytic Choriomeningitis Virus. 26 , 27 Since these T cells are not functional in our model, further studies are needed to understand whether anti-PD1 treatment may be beneficial in patients possessing a substantial frequency of this T-cell subset. Differently, combined immunotherapy expanded anti-tumor functional CD8 + T cell with low levels of CD28 and PD-1.…”
Section: Discussionmentioning
confidence: 99%
“…GC Tfh cells are not only highly activated cells that are good targets for HIV‐1 infection but are also located in close proximity to FDCs, which are an important reservoir of infectious virus and can readily transmit infection to Tfh cells 180, 181, 182, 183. Virus replication in GC Tfh cells may also be facilitated by the limited ability of antiviral CD8 + T cells to enter B‐cell follicles,168, 171, 175, 179, 184 although recent studies in the lymphocytic choriomeningitis virus (LCMV) mouse model show that persisting virus can be cleared from Tfh cells and B cells by a CXCR5 +  CD8 + T‐cell population that is able to enter B‐cell follicles,185, 186, 187 raising the intriguing prospect that if an analogous antiviral CD8 + T‐cell population expressing sufficiently high levels of CXCR5 could be induced in humans, this may enable targeting of Tfh cells that harbor persistent HIV‐1 such as the latent pool.…”
Section: T Follicular Helper Cells and Their Role In Bnab Inductionmentioning
confidence: 99%
“…T cells do not exhaust uniformly during chronic diseases or cancer, but instead specific subsets with different memory and proliferative potentials emerge after exposure to persistent antigen [122,123].…”
Section: T Cell Exhaustionmentioning
confidence: 99%