Article

Regulation of antigen-specific CD8+ T cell homeostasis by perforin and interferon-γ

Department of Microbiology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.
Science (Impact Factor: 33.61). 12/2000; 290(5495):1354-8. DOI: 10.1126/science.290.5495.1354
Source: PubMed

ABSTRACT

T cell memory depends on factors that regulate expansion and death of these cells after antigenic stimulation. Mice deficient in perforin and interferon-gamma (IFN-gamma) exhibited increased expansion, altered immunodominance, and decreased death of antigen-specific CD8+ T cells after infection with an attenuated strain of Listeria monocytogenes, which was cleared from these mice. Expansion of CD8+ T cells was controlled by perforin, whereas IFN-gamma regulated immunodominance and the death phase. Thus, perforin and IFN-gamma regulate distinct elements of CD8+ T cell homeostasis independently of their role as antimicrobial effector molecules.

0 Followers
 · 
6 Reads
  • Source
    • "Tumor cells were immunogenic and induced tolerance to a cellular anti-tumor immunity, not able to protect mice from tumor development (17). The lower tumor-specific proliferative response of pfn-deficient CTL was surprising as several studies showed that perforin-deficient mice exhibited an exaggerated CTL immune response upon infections (18–20). The mechanisms of partial tolerance induction have to be investigated but we speculate that in tumor-bearing mice, perforin-deficient CD8+ T cells were exhausted due to tumor environment. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Our newly generated murine tumor dendritic cell (MuTuDC) lines, generated from tumors developing in transgenic mice expressing the simian virus 40 large T antigen (SV40LgT) and GFP under the DC specific promoter CD11c, reproduce the phenotypic and functional properties of splenic wild type CD8α(+) conventional DCs. They have an immature phenotype with low co-stimulation molecule expression (CD40, CD70, CD80, and CD86) that is upregulated after activation with toll-like receptor ligands. We observed that after transfer into syngeneic C57BL/6 mice, MuTuDC lines were quickly rejected. Tumors grew efficiently in large T transgene-tolerant mice. To investigate the immune response toward the large T antigen that leads to rejection of the MuTuDC lines, they were genetically engineered by lentiviral transduction to express luciferase and tested for the induction of DC tumors after adoptive transfer in various gene deficient recipient mice. Here, we document that the MuTuDC line was rejected in C57BL/6 mice by a CD4 T cell help-independent, perforin-mediated CD8 T cell response to the SV40LgT without pre-activation or co-injection of adjuvants. Using depleting anti-CD8β antibodies, we were able to induce efficient tumor growth in C57BL/6 mice. These results are important for researchers who want to use the MuTuDC lines for in vivo studies.
    Full-text · Article · Jul 2014 · Frontiers in Immunology
  • Source
    • "Evidence in the literature suggests that the contraction of the CD8 T cell response is pre-programmed early after infection and takes place independently of pathogen clearance [54]. Previous reports have identified that IFN-γ directs the contraction phase of the CD8 T cell response to Listeria infection [55]. In the present study, we observed a major contraction of the CD8 T cell response between day 9 and 12 independently of T cell intrinsic TNF/TNFR2, however, the presence of TNF/TNFR2 on the T cells augments this contraction phase. "
    [Show abstract] [Hide abstract]
    ABSTRACT: TNF is an important inflammatory mediator and a target for intervention. TNF is produced by many cell types and is involved in innate inflammation as well as adaptive immune responses. CD8 T cells produce TNF and can also respond to TNF. Deficiency of TNF or TNFR2 has been shown to affect anti-viral immunity. However, as the complete knockout of TNF or its receptors has effects on multiple cell types as well as on lymphoid architecture, it has been difficult to assess the role of TNF directly on T cells during viral infection. Here we have addressed this issue by analyzing the effect of CD8 T cell intrinsic TNF/TNFR2 interactions during respiratory influenza infection in mice, using an adoptive transfer model in which only the T cells lack TNF or TNFR2. During a mild influenza infection, the capacity of the responding CD8 T cells to produce TNF increases from day 6 through day 12, beyond the time of viral clearance. Although T cell intrinsic TNF is dispensable for initial expansion of CD8 T cells up to day 9 post infection, intrinsic TNF/TNFR2 interactions potentiate contraction of the CD8 T cell response in the lung between day 9 and 12 post infection. On the other hand, TNF or TNFR2-deficient CD8 T cells in the lung express lower levels of IFN-γ and CD107a per cell than their wild type counterparts. Comparison of TNF levels on the TNFR2 positive and negative T cells is consistent with TNF/TNFR2 interactions inducing feedback downregulation of TNF production by T cells, with greater effects in the lung compared to spleen. Thus CD8 T cell intrinsic TNF/TNFR2 interactions fine-tune the response to influenza virus in the lung by modestly enhancing effector functions, but at the same time potentiating the contraction of the CD8 T cell response post-viral clearance.
    Preview · Article · Jul 2013 · PLoS ONE
  • Source
    • "Ainsi, un déficit de la réponse cytotoxique entraverait, d'une part, le processus de contraction qui suit normalement l'expansion des lymphocytes T CD8 + activés, et d'autre part, il modifierait la répartition des populations T CD8 + immunodominantes, expliquant la prédominance de certains clones lymphocytaires chez ces patients. En faveur de cette hypothèse, les souris déficientes en perforine et en interféron-g développent, à l'occasion d'une stimulation infectieuse , une hyperlymphocytose fruit d'une expansion, suivie d'un défaut de contraction de cette population lymphocytaire [12] [13]. Par ailleurs, la cinétique d'élimination plus lente des antigènes infectieux au cours d'un déficit immunitaire pourrait favoriser l'expansion anormale des cellules T CD8 + [12]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Une expansion polyclonale de lymphocytes T CD8+/CD57+ peut s’observer au cours de différentes situations pathologiques, telles qu’une infection virale chronique, des cytopénies immunologiques, une maladie systémique, une réaction du greffon contre l’hôte chronique ou un déficit immunitaire primitif ou acquis. Cette population de lymphocytes résulte de la stimulation chronique de lymphocytes CD8+/CD28+ par des antigènes exogènes (d’origine infectieuse), autologues ou allogéniques, aboutissant à la génération de lymphocytes CD8+ qui perdent progressivement leur capacités de prolifération dans des conditions standards par perte de l’expression de l’antigène CD28. En parallèle, ils expriment à leur surface l’antigène CD57. Les lymphocytes T CD8+/CD57+correspondent à des lymphocytes T cytotoxiques activés, au stade ultime de leur différenciation et dont le développement fait suite à une stimulation antigénique chronique. Ils ont habituellement perdu leur potentiel cytotoxique pour avoir des caractéristiques fonctionnelles de lymphocytes T régulateurs. Les tableaux cliniques résultant d’une expansion de lymphocytes T CD8+/CD57+se caractérisent par l’infiltration d’un ou plusieurs organes. Une expansion polyclonale de lymphocytes T CD8+/CD57+ peut être également associée à des neutropénies chroniques idiopathiques. Une expansion de lymphocytes T CD8+/CD57+doit être suggérée devant des tableaux cliniques évocateurs comme une organomégalie chez un patient infecté par le virus de l’immunodéficience humaine (VIH) ou une alvéolite lymphocytaire chez un patient allogreffé. Le rôle de cette expansion peut être évoqué chez des patients ayant des cytopénies d’origine inconnue, surtout s’il existe un déficit immunitaire sous-jacent. L’identification de cette expansion aboutit également à une sanction thérapeutique puisque les tableaux d’infiltration viscérale par des lymphocytes T CD8+/CD57+peuvent répondre remarquablement à des immunosuppresseurs ou immunomodulateurs. La recherche d’une expansion de lymphocytes T CD8+/CD57+ est ainsi un outil diagnostique original encore peu connu et dont l’intérêt en pratique clinique nécessite d’être mieux précisé.
    Full-text · Article · Mar 2013 · La Presse Médicale
Show more