Repertoire Development and the Control of Cytotoxic/Effector Function in Human <i>γ</i><i>δ</i> T Cells

Urban, Elizabeth; Chapoval, Andrei I.; Pauza, C. David

doi:10.1155/2010/732893

Cited by 28 publications

(30 citation statements)

References 165 publications

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“…The functionally tolerated variability in CDR3 sequences and lengths reported in the present study support the observation that ␥9␦2T-cell responses to phosphoantigen stimulation do not further select for defined CDR3 sequences. 38,39 Consistent with this, we observed identical dose-response kinetics in pamidronate titration experiments, although the magnitude of response differed significantly. The observation that equal pamidronate EC 50 s were calculated for all responsive ␥9␦2TC-transduced cells that only differ in their CDR3 domains indicates that ␥9 and ␦2CDR3 binding does not involve substrates directly regulated by pamidronate.…”

supporting

confidence: 86%

γ9 and δ2CDR3 domains regulate functional avidity of T cells harboring γ9δ2TCRs

Gründer¹,

Dorp²,

Hol³

et al. 2012

Blood

107

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Immunotherapy with innate immune cells has recently evoked broad interest as a novel treatment option for cancer patients. ␥9␦2T cells in particular are emerging as an innate cell population with high frequency and strong antitumor reactivity, which makes them and their receptors promising candidates for immune interventions. However, clinical trials have so far reported only limited tumor control by adoptively transferred ␥9␦2T cells. As a potential explanation for this lack of efficacy, we found unexpectedly high variability in tumor recognition within the physiologic human ␥9␦2T-cell repertoire, which is substantially regulated by the CDR3 domains of individual ␥9␦2TCRs. In the present study, we demonstrate that the reported molecular requirements of CDR3 domains to interact with target cells shape the physiologic ␥9␦2T-cell repertoire and, most likely, limit the protective and thera- IntroductionImmunotherapy with innate immune cells has become widely used because this approach obviates the need to match a cellular product to a defined HLA haplotype, allowing adoptive immunotherapies to be used in virtually any cancer patient without extensive in vitro selection or manipulation of the cellular product. 1-4 ␥9␦2T cells are promising as an innate cell population for this purpose because they are usually observed at high frequencies in the human peripheral blood and provide a strong antitumor reactivity against various solid and hematologic cancers. 5 However, within ␥9␦2T-cell populations, individual clones display great diversity in the repertoire because of the activating or inhibitory receptors expressed. 6 Selecting innate cell products for certain cell types, such as those with a low level of inhibitory receptors, therefore seems plausible, especially considering the limited efficacy of adoptively transferred innate immune cells in clinical trials. 7,8 An alternative proposal is to engineer cells to express defined activating innate receptors that mediate strong antitumor reactivity, such as a defined ␥9␦2TCR, 9 which could pave the way for readily available and more effective cellular products. However, the molecular details of how a ␥9␦2TCR interacts with its target are not fully understood, making it challenging to select defined ␥9␦2T cells or to engineer T cells with defined ␥9␦2TCRs.In "classic" immunoreceptors such as ␣␤TCRs or Igs, the complementary determining regions (CDRs) determine affinity and specificity for a specific (peptide) epitope. V(D)J recombination allows the creation of a highly variable CDR repertoire ensuring recognition of an immense collection of antigens. ␥9␦2T cells also possess a rearranged TCR that mediates recognition. The phosphoantigen isopentenyl pyrophosphate (IPP) has been suggested to be a key player in ␥9␦2TCR-mediated activation, 5,10,11 but no direct interaction between a ␥9␦2TCR and IPP or any other phosphoantigen has ever been demonstrated. It was previously suggested that positively charged residues within the ␥9␦2TCR are crucial for the response to negatively...

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supporting

confidence: 86%

γ9 and δ2CDR3 domains regulate functional avidity of T cells harboring γ9δ2TCRs

Gründer¹,

Dorp²,

Hol³

et al. 2012

Blood

107

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“…The two antibodies γδTCR and T19 were used as markers of γδT cells (Evans et al 1994), and the distribution of γδT cells in the PPs agrees with that of T19 antigen expression. The presence of γδT cells is mainly restricted to the intraepithelial space, such as in the small and large intestine (Matsumoto et al 1999;Urban et al 2010). Most γδT cells do not express CD4 and CD8 receptors, which are needed for self-recognition via MHC class II and class I, respectively (O'Brien and Born 2010).…”

Section: Discussionmentioning

confidence: 99%

Distribution of immune cells and expression of interleukin receptors in ileal Peyer’s patches of calves

2011

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Newborn calves lack a mature immune system. The immune system develops with age, but the role of the expression of cytokine receptors in the development of immune cells of Peyer's patches (PPs) in the intestines of calves in the first 2 months has not yet been elucidated. In this study, the distribution of immune cells and the expression of interleukin (IL) receptors (R) in the ileal PPs of newborn and 2-month-old calves were investigated immunohistochemically with monoclonal antibodies against bovine CD4, CD8, IgM, γδTCR, T19, WC3, WC5, and WC6 antigens. The expression of ILRs was examined with antibodies against CD25 (IL-2Rα), IL-2Rγ, IL-4R, IL-6R, IL-10R, and IL-13R antigens. CD4(+), CD8(+), γδTCR(+), T19(+), and WC6(+) cells were found to be more widely distributed in the ileal PPs of 2-month-old calves than in those of newborn calves. Moreover, the expression of CD25 (IL-2Rα), IL-4R, and IL-13R in the ileal PPs of 2-month-old calves was more prominent than that in newborn calves. These data suggest that the immune system of calves at 2 months of age is developed by reactions to foreign antigens and aging.

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“…Unlike αβT cells, γδ T cells represent a minor subset of T cells that does not require self-majorhistocompatibility complex (MHC)-restricted priming (1). γδ T cells are believed to serve as a bridge, connecting the innate and adaptive immune responses (1).…”

Section: Introductionmentioning

confidence: 99%

“…γδ T cells are believed to serve as a bridge, connecting the innate and adaptive immune responses (1). Following infection by microbial pathogens, γδ T cells appear to be the first T cells tomigrateto the lung (2).…”

Section: Introductionmentioning

confidence: 99%

Characterization of γδ T cells in patients with non-small cell lung cancer

Bao

2017

Oncology Letters

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Repertoire Development and the Control of Cytotoxic/Effector Function in Human γδ T Cells

Cited by 28 publications

References 165 publications

γ9 and δ2CDR3 domains regulate functional avidity of T cells harboring γ9δ2TCRs

γ9 and δ2CDR3 domains regulate functional avidity of T cells harboring γ9δ2TCRs

Distribution of immune cells and expression of interleukin receptors in ileal Peyer’s patches of calves

Characterization of γδ T cells in patients with non-small cell lung cancer

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