T cell immunity after a viral infection versus T cell tolerance induced by soluble viral peptides

Kyburz, Diego; Aichele, Peter; Speiser, Daniel E.; Hengartner, Hans; Rm, Zinkernagel; Pircher, Hanspeter

doi:10.1002/eji.1830230834

Cited by 245 publications

(173 citation statements)

References 44 publications

(5 reference statements)

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“…Thy1.1 1 P14 TCR-tg mice (B6; D2-Tg(TcrLCMV)318Sdz/JDvsJ) specific for aa 33-41 (gp33 epitope) of the LCMV glycoprotein [34] and B6.Thy1.1 mice (B6.PLThy1 a ) were bred locally. Female or male mice were used at 8-20 wk of age.…”

Section: Methodsmentioning

confidence: 99%

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

2008

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We determined the efficacy of in vitro expanded P14 TCR transgenic CD8 T cells to mediate tumor cell elimination and to protect against viral infection in mice. Contrary to previous studies, an adoptive transfer model without lymphodepletion, vaccination or cytokine treatment was used. Antigen-activated P14 T cells cultured in IL-2-containing medium for 7 days (P14 IL-2 ) exhibited potent effector cell functions in vitro but did not confer protection against melanoma growth or viral infection. In contrast, P14 T cells cultured in IL-15 (P14 ) were highly effective in vivo although they displayed only moderate effector functions in vitro. Therapeutic efficacy correlated with the survival of the transferred T cells in the recipients: P14 IL-2 cells disappeared rapidly whereas P14 IL-15 cells persisted for prolonged time. Decreasing the IL-2 concentration in the culture media improved in vivo survival and efficacy but also lowered the cell yield of the cultures. Finally, we could extend the findings with monoclonal P14 T cells to polyclonal CD8 T cells. Thus, in vitro expansion of antigen-specific CD8 T cells in IL-15 allowed the generation of substantial numbers of T cells without inducing terminally differentiated effector cells that turned out to be unfavorable in the transfer model examined here.Key words: Cytotoxic T cells . Rodent . Tumor immunity . Viral IntroductionAdoptive transfer of antigen-specific CD8 T cells into hosts represents a promising approach to treat tumors and viral infections [1][2][3][4]. To generate sufficient numbers of T cells for this therapy, T cells have to be stimulated and expanded in vitro. In most protocols used today, IL-2 is added to the culture medium to ensure T-cell proliferation, differentiation and survival. Besides IL-2, IL-15 also supports CD8 T-cell growth [5]; however, the phenotype and the functional activity of IL-2-versus IL-15-cultured CD8 T cells differ considerably. Manjunath et al. [6] were the first to show that CD8 T cells from P14 TCR-tg mice specific for gp33 epitope of lymphocytic choriomeningitis virus (LCMV) acquired an effector memory phenotype with high cytolytic activity when cultured in the presence of IL-2 whereas addition of IL-15 led to a central memory phenotype with low effector cell functions. Further analysis in the same TCR transgenic system revealed that these two cytokines were equivalent mitogens for antigen-stimulated CD8 T cells but that IL-2 was more potent in inducing amino acid uptake and protein synthesis [7].For adoptive T-cell therapy, it is important to generate CD8 T cells in vitro, which are efficient in inducing tumor regression or virus clearance in vivo. The degree of specific target cell lysis and the amount of antigen-triggered IFN-g production are frequently used to predict the efficacy of CD8 T cells in vivo. However, several recent studies in the pmel-1 TCR-tg model specific for the self/tumor antigen gp100 of B16 melanoma cells indicated that antigen-stimulated CD8 T cells with a less differentiated phenotype were sup...

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Section: Methodsmentioning

confidence: 99%

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

2008

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“…P14 TCR-tg mice (line 318 [46]) specific for amino acids 33-41 (GP33 epitope) of the LCMV glycoprotein in association with H-2D b , ALB1-tg mice [37] expressing the LCMV GP33 epitope as a transgene under the control of the albumin promoter and B6 mice deficient in perforin [47] and IFN-c [48] have been described previously. Female or male mice were used at 8-16 wks of age.…”

Section: Methodsmentioning

confidence: 99%

Solid tumors “melt” from the inside after successful CD8 T cell attack

Blohm¹,

Potthoff²,

Kogel³

et al. 2006

Eur J Immunol

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Adoptive transfer of tumor-specific T cells represents a promising approach for cancer immunotherapy. Here, we visualized the anti-tumor response of CD8 T cells from P14 TCR-transgenic mice specific for the model antigen GP33 by immunohistology. P14 T cells, adoptively transferred into tumor-bearing hosts, induced regression of established 3LL-A9 GP33 and MCA102 GP33 tumors that express GP33 as a tumor-associated model antigen. Strikingly, the visible effects of P14 T cell attack, such as the destruction of the tumor vasculature and accumulation of granulocytes, were predominantly detected inside the tumor mass. In regressing tumors, P14 T cells were found in the intact rim zone but not in central areas that were infiltrated with granulocytes and lacked CD31 + endothelial cells. The rim of P14 T cell-treated tumors showed an increase in vascular density and decrease in hypoxia compared to untreated tumors. Hypoxic areas of tumors are known to exhibit decreased sensitivity to radiation therapy or chemotherapy. Thus, our data also imply that adoptive transfer of tumor-specific CD8 T cells might synergize with radiation therapy or chemotherapy in the elimination of solid tumors in vivo.

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“…The following reagents were used: SIINFEKL (OVA 257-264 ) [57], KAVYNFATM (gp33 [33][34][35][36][37][38][39][40][41] ) [63] from Pineda (Berlin, Germany), ovalbumin (grade II and VII) and saponin from Sigma (Deisenhofen, Germany). mAb conjugated to different fluorochroms or biotin were purchased from BD Biosciences (Heidelberg, Germany; San Diego, CA) and eBioscience (San Diego, CA); anti-CD44-AlexaFluor 405 Ab was from Caltag (Hamburg, Germany; Burlingame, CA).…”

Section: Reagents and Antibodiesmentioning

confidence: 99%

Immediate antigen‐specific effector functions byTCR‐transgenic CD8⁺ NKT cells

Wingender¹,

Berg²,

Jüngerkes³

et al. 2006

Eur J Immunol

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Only recently have natural antigens for CD1d-dependent, invariant Va14 + natural killer T (iNKT) cells been identified. Similar data for CD1d-independent and CD8 + NKT cell populations are still missing. Here, we show that the MHC class I-restricted CD8 + TCRtransgenic mouse lines OT-I, P14 and H-Y contain a significant proportion of transgenic CD8 + NK1.1 + T cells. In liver, most of NK1.1 + T cells express CD8aa homodimers. Transgenic NKT cells did not bind invariant Va14-to-Ja18 TCR rearrangement (Va14i)-specific CD1d/a-galactosylceramide tetramers and the frequency of iNKT cells was severely reduced. The activated cell surface phenotype and the distribution of transgenic NKT cells in vivo were similar to that reported for iNKT cells. The OT-I and P14 CD8 + NKT cells recognized their cognate antigen in the context of H2-K b and produced cytokines shortly after TCR stimulation. Importantly, transgenic NKT cells exerted immediate antigen-specific cytotoxicity in vitro and in vivo. Our results demonstrate the presence of transgenic CD8 + NKT cells in MHC class I-restricted TCR-transgenic animals, which are endowed with rapid antigen-specific effector functions. These data imply that experiments studying naive T cell function in TCR-transgenic animals should be interpreted with caution, and that such animals could be utilized for studying CD8 + NKT cell function in an antigen-specific manner.

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T cell immunity after a viral infection versus T cell tolerance induced by soluble viral peptides

Cited by 245 publications

References 44 publications

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

Solid tumors “melt” from the inside after successful CD8 T cell attack

Immediate antigen‐specific effector functions byTCR‐transgenic CD8⁺ NKT cells

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T cell immunity after a viral infection versus T cell tolerance induced by soluble viral peptides

Cited by 245 publications

References 44 publications

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

Solid tumors “melt” from the inside after successful CD8 T cell attack

Immediate antigen‐specific effector functions byTCR‐transgenic CD8+ NKT cells

Contact Info

Product

Resources

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Immediate antigen‐specific effector functions byTCR‐transgenic CD8⁺ NKT cells