Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors

Teague, Ryan M.; Sather, Blythe; Sacks, Jilian A.; Huang, Maria Z.; Dossett, Michelle L.; Morimoto, Junko; Tan, Xiaoxia; Sutton, Susan; Cooke, M.; Öhlén, Claes; Greenberg, Philip D.

doi:10.1038/nm1359

Cited by 218 publications

(181 citation statements)

References 35 publications

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“…Nevertheless, homeostatic proliferation was able to prevent hyporesponsiveness of antitumor T cells and also to reverse established hyporesponsiveness of peptide-anergized 2C cells, so the homeostatic proliferation process maintained and/or restored T cell function in both settings. Consistent with our results, a recent report has indicated that exogenous IL-15 also can reverse T cell anergy in vivo (57).…”

Section: Discussionsupporting

confidence: 93%

Homeostatic Proliferation as an Isolated Variable Reverses CD8+ T Cell Anergy and Promotes Tumor Rejection

Brown

Blank

Kline

et al. 2006

The Journal of Immunology

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Although recent work has suggested that lymphopenia-induced homeostatic proliferation may improve T cell-mediated tumor rejection, there is little direct evidence isolating homeostatic proliferation as an experimental variable, and the mechanism by which improved antitumor immunity occurs via homeostatic proliferation is poorly understood. An adoptive transfer model was developed in which tumor-specific 2C/RAG2−/− TCR transgenic CD8+ T cells were introduced either into the lymphopenic environment of RAG2−/− mice or into P14/RAG2−/− mice containing an irrelevant CD8+ TCR transgenic population. RAG2−/−, but not P14/RAG2−/− recipients supported homeostatic proliferation of transferred T cells as well as tumor rejection. Despite absence of tumor rejection in P14/RAG2−/− recipients, 2C cells did become activated, as reflected by CFSE dilution and CD44 up-regulation. However, these cells showed poor IFN-γ and IL-2 production upon restimulation, consistent with T cell anergy and similar to the hyporesponsiveness induced by administration of soluble peptide Ag. To determine whether homeostatic proliferation could uncouple T cell anergy, anergic 2C cells were transferred into RAG−/− recipients, which resulted in vigorous homeostatic proliferation, recovery of IL-2 production, and acquisition of the ability to reject tumors. Taken together, our data suggest that a major mechanism by which homeostatic proliferation supports tumor rejection is by maintaining and/or re-establishing T cell responsiveness.

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Section: Discussionsupporting

confidence: 93%

Homeostatic Proliferation as an Isolated Variable Reverses CD8+ T Cell Anergy and Promotes Tumor Rejection

Brown

Blank

Kline

et al. 2006

The Journal of Immunology

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“…These CD44 hi CD122 hi CD8 ϩ T cells may have functions in the immunosurveillance of tumor cells. Teague et al (28) described the ability of IL-15-cultured CD8 ϩ T cells to inhibit tumor growth. In their interpretation, IL-15 overcame immunotolerance mechanisms.…”

Section: Resultsmentioning

confidence: 99%

ITK and IL-15 support two distinct subsets of CD8⁺T cells

Dubois

Waldmann

Müller

2006

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

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(3,4). In addition, IL-15 Ϫ/Ϫ mice are unable to maintain antigen-specific CD8 ϩ memory T cells after immunization with viruses (5, 6). These defects point to functions of IL-15 in both adaptive and innate immunity.Antigenic stimulation of naïve CD8 ϩ T cells induces the high expression of CD44 (7,8), for which all CD44 hi CD8 ϩ T cells were termed ''memory phenotype'' cells. An injection of IL-15 into mice induces the expansion of these CD8 ϩ CD44 hi T cells independent of antigenic stimulation (9, 10). It was concluded that IL-15 directly supports the maintenance of CD8 ϩ memory T cells. However, a number of other treatments also selectively increase the number of CD8 ϩ CD44 hi T cells without antigenic stimulation that include ''bystander'' proliferation in response to poly I:C or LPS (11), proliferation after an injection of mature dendritic cells (12), or lymphopenia-induced proliferation after CD8 ϩ T cell transfer into irradiated hosts (13,14). Because the presence of antigen should be a necessity for the generation of true memory cells, subsets of CD8 ϩ CD44 hi T cells may have functions other than in CD8 memory.Mice with a deletion in the tec kinase ITK have reduced numbers of both peripheral CD4 ϩ and CD8 ϩ T cells (15). Among the CD8 ϩ T cells that are present, the majority express high levels of CD44 and CD122 (16). The function of these cells has not been fully elucidated. Defects in CD8 ϩ T cells in ITK Ϫ/Ϫ mice include positive and negative selection, cytokine production, TCR engagement-induced proliferation, and reduced cytolytic activity against allogenic splenocytes and against virally infected cells (15).Here we show that IL-15 and ITK support two distinct subsets of CD8 ϩ T cells that are present in both the thymus and the periphery. The two subpopulations of CD8 ϩ T cells appear to have independent functions in the periphery. ResultsCD8 ؉ T Cells in ITK ؊/؊ Mice Depend on IL-15. CD8 ϩ T cells in ITK Ϫ/Ϫ mice and in IL-15 Ϫ/Ϫ mice are phenotypically different. In particular, CD8 ϩ T cells in ITK Ϫ/Ϫ mice express high levels of CD44 and CD122. In contrast, IL-15 Ϫ/Ϫ CD8 ϩ T cells express low levels of CD44 and CD122. This difference could be caused by a dysregulation of both surface markers. Alternatively, ITK and IL-15 could support two distinct subsets of CD8 ϩ T cells. To distinguish between these possibilities, we determined whether the CD44 hi CD122 hi CD8 ϩ T cells in ITK Ϫ/Ϫ mice depend on IL-15. We initially injected the antibody ⌻m␤1, which inhibits the activity of transpresented IL-15 on the IL-2͞15R␤ chain. One week after a 50-g injection of ⌻m␤1, the percentage of peripheral blood CD8 ϩ T cells in ITK Ϫ/Ϫ mice was reduced to Ͻ15% compared with untreated wild-type mice (Fig. 1A). All of the remaining CD8 ϩ T cells expressed high levels of CD44 and CD122 ( Fig. 1 A and data not shown).We then generated mice that are deficient in both ITK and IL-15. CD8 ϩ CD44 hi CD122 hi T cells represent 10-30% of all CD8 ϩ T cells in young wild-type mice. As described previously (3) and as shown i...

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“…FBL, a Friend virus-induced erythroleukemia of C57BL/6 (H-2 b ) origin that expresses MHC class I and FMuLV Gag-encoded products, has been previously described (61). The FMuLV Gag peptide (CCLCLTVFL) recognized by TCRgag CD8 + T cells was purchased from Pi Proteomics.…”

Section: Methodsmentioning

confidence: 99%

Abrogating Cbl-b in effector CD8+ T cells improves the efficacy of adoptive therapy of leukemia in mice

Stromnes¹,

Blattman²,

Tan³

et al. 2010

J. Clin. Invest.

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Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors

Cited by 218 publications

References 35 publications

Homeostatic Proliferation as an Isolated Variable Reverses CD8+ T Cell Anergy and Promotes Tumor Rejection

Homeostatic Proliferation as an Isolated Variable Reverses CD8+ T Cell Anergy and Promotes Tumor Rejection

ITK and IL-15 support two distinct subsets of CD8⁺T cells

Abrogating Cbl-b in effector CD8+ T cells improves the efficacy of adoptive therapy of leukemia in mice

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Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors

Cited by 218 publications

References 35 publications

Homeostatic Proliferation as an Isolated Variable Reverses CD8+ T Cell Anergy and Promotes Tumor Rejection

Homeostatic Proliferation as an Isolated Variable Reverses CD8+ T Cell Anergy and Promotes Tumor Rejection

ITK and IL-15 support two distinct subsets of CD8+T cells

Abrogating Cbl-b in effector CD8+ T cells improves the efficacy of adoptive therapy of leukemia in mice

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ITK and IL-15 support two distinct subsets of CD8⁺T cells