Intrinsic and extrinsic control of effector T cell survival and memory T cell development

Hand, Timothy W.; Kaech, Susan M.

doi:10.1007/s12026-008-8027-z

Cited by 43 publications

(45 citation statements)

References 159 publications

(209 reference statements)

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“…Conventional CD8 þ T-cell responses rapidly contract after the peak of the response has been reached, and levels of CD8 þ T cells that remain after contraction are generally around 5% of peak levels. 41,42 In all our previous studies, immune responses induced by DNA tattoo showed similar kinetics, with contraction being close to complete about 1 week after the peak of the response. 16,38 In contrast, upon tattooing TTFC-E7-encoding DNA vaccines, we consistently observed that contraction of the induced CD8 þ T-cell response was delayed for about 3 weeks, and that the remaining frequencies after 4 weeks were still around 20% of the initial peak height (Fig.…”

Section: Discussionsupporting

confidence: 58%

Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

Oosterhuis

Öhlschläger

Berg

et al. 2011

Intl Journal of Cancer

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To allow vaccination irrespective of HLA type, DNA vaccines encoding full-length antigens are required. However, here, we demonstrate that the immunogenicity of DNA vaccines encoding the full-length human papillomavirus (HPV) type 16 E7 and E6 proteins is highly reduced compared to vaccines encoding only the immunodominant epitope. Furthermore, the low remaining immunogenicity is essentially lost for both E7 and E6 when a nononcogenic ''gene-shuffled" variant is utilized. To address these issues, we tested whether alterations in transgene design can restore the immunogenicity of full-length and geneshuffled DNA vaccines. Remarkably, genetic fusion of E7 with tetanus toxin fragment C (TTFC) resulted in a dramatic increase in immunogenicity both for the full-length and the gene-shuffled version of E7. Moreover, the TTFC fusion vaccines were more immunogenic than a vaccine encoding a fusion of E7 and mycobacterial heat shock protein-70, which has recently been tested in a clinical trial. Interestingly, vaccination with these TTFC fusion vaccines also resulted in extremely persistent T-cell responses. The E7-specific CD8 1 T cells induced by TTFC fusion vaccines were functional in terms of IFN-c production,formation of immunological memory, in vivo cytolytic activity and tumor eradication. Finally, we show that genetic fusion with TTFC also improves the immunogenicity of a gene-shuffled E6 DNA vaccine. These data demonstrate that genetic fusion with tetanus toxin fragment C can dramatically improve the immunogenicity of full-length and gene-shuffled DNA vaccines. The DNA fusion vaccines developed here will be evaluated for the treatment of HPV-positive carcinomas in future studies.Persistent infection with ''high-risk'' human papillomavirus (HPV) genotypes is strongly associated with the development of anogenital cancers. 1,2 Of the ''high-risk'' genotypes, HPV 16 alone is known to be responsible for about half of the cervical cancer cases worldwide.3 Because persistent expression of the oncogenic HPV proteins E6 and E7 is required for carcinogenesis, these viral antigens are ideal targets for immunotherapeutic interventions. As E6 and E7 are solely expressed intracellularly, such therapeutic interventions should induce cellular immune responses to control existing HPV-induced lesions. 3,4 DNA vaccination forms an attractive approach for the induction of cellular immune responses as the DNA-encoded antigens are by definition produced intracellularly. Furthermore, DNA vaccines are safe, easy to produce, stable and do not suffer from the drawback of preexisting immunity or induction of antivector immunity. 5,6 In murine models, numerous DNA vaccines directed against either HPV 16 E6 or E7 have been tested with promising results.7-13 However, to date, the clinical translation of these approaches has met little success.14,15 Recently, we developed a novel DNA vaccination strategy named DNA tattoo vaccination that can potentially overcome this translational block. This strategy was shown to lead to the rapid induction of...

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Section: Discussionsupporting

confidence: 58%

Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

Oosterhuis

Öhlschläger

Berg

et al. 2011

Intl Journal of Cancer

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“…The gating strategy of CD25 versus CD127 allowed the identification of regulatory T-cells (CD251CD127low) and the separation of cell populations that express CD127 at very high or low levels, respectively. In this panel, regulatory T-cell activation was assessed by anti-HLA-DR staining and the CD4 T-cell activation was estimated based on CD25 surface marker expression (14,26,28,29). Additionally, regulatory T-cells can be further divided in na€ ıve and memory regulatory T-cells and were calculated by CD31CD41 AND CD251CD127low AND CD45RO (high/low) (14).…”

Section: Panel Design and Gating Strategymentioning

confidence: 99%

Eight-color immunophenotyping of T-, B-, and NK-cell subpopulations for characterization of chronic immunodeficiencies

et al. 2014

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“…The exact biochemical mechanism governing the survival of memory cells and apoptosis of the majority of effector cells is not well understood (1). As naïve T cells differentiate into effector and memory T cells, cytokines play a key role in their differentiation and survival.…”

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confidence: 99%

Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival

Hand

Cui²,

Jung³

et al. 2010

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

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194

191

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During viral infection, effector CD8 T cells contract to form a population of protective memory cells that is maintained by IL-7 and IL-15. The mechanisms that control effector cell death during infection are poorly understood. We investigated how short-and long-lived antiviral CD8 T cells differentially used the survival and cell growth pathways PI3K/AKT and JAK/STAT5. In response to IL-15, long-lived memory precursor cells activated AKT significantly better than shortlived effector cells. However, constitutive AKT activation did not enhance memory CD8 T-cell survival but rather repressed IL-7 and IL-15 receptor expression, STAT5 phosphorylation, and BCL2 expression. Conversely, constitutive STAT5 activation profoundly enhanced effector and memory CD8 T-cell survival and augmented homeostatic proliferation, AKT activation, and BCL2 expression. Taken together, these data illustrate that effector and memory cell viability depends on properly balanced PI3K/AKT signaling and the maintenance of STAT5 signaling.apoptosis | cytokine signaling | interleukin 15 | interleukin 7 | lymphocytic choriomeningitis virus M emory CD8 T cells form from a much larger effector population and provide long-term immunity against subsequent infections via rapid reactivation. The exact biochemical mechanism governing the survival of memory cells and apoptosis of the majority of effector cells is not well understood (1). As naïve T cells differentiate into effector and memory T cells, cytokines play a key role in their differentiation and survival. IL-2, IL-7, and IL-15 promote the expansion and survival of activated T cells (2). As memory CD8 T cells form following acute viral infection, two of these cytokines, IL-15 and IL-7, direct memory T cell survival and homeostasis (3, 4). Downstream of their specific receptors, IL-7 and IL-15 activate two primary pathways: janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) and phosphoinositide 3-kinase (PI3K)/AK-transforming (AKT). Activation of these two pathways results in decreased levels of proapoptotic proteins, increased expression of antiapoptotic genes such as BCL2, and activation of cellular growth and proliferation pathways regulated by mTOR and cyclins (5). The balance between these pro-and antiapoptotic factors controls the survival of CD8 T cells after immunization (6).Early models predicted that effector CD8 T-cell contraction was a result of deprivation of T-cell growth factor cytokines that wane during the later stages of infection and that survival was determined via the stochastic interaction of effector T cells with these cytokines. However, effector CD8 T cells are a heterogeneous population composed of cells with varying intrinsic potential for survival and differentiation into memory cells (3,7,8). During several types of infections [such as lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), Listeria monocytogenes, and Toxoplasma gondii], most of the effector CD8 T cells terminally differentiate and become short-lived, but ...

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Intrinsic and extrinsic control of effector T cell survival and memory T cell development

Cited by 43 publications

References 159 publications

Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

Eight-color immunophenotyping of T-, B-, and NK-cell subpopulations for characterization of chronic immunodeficiencies

Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival

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