CD8 is needed for development of cytotoxic T but not helper T cells

Fung-Leung, Wai-Ping; Schilham, Marco W.; Rahemtulla, Amin; Kündig, Thomas M.; Vollenweider, Maja; Potter, Julia M.; Ewijk, Willem van; Mak, Tak W.

doi:10.1016/0092-8674(91)90462-8

Cited by 498 publications

(294 citation statements)

References 41 publications

Supporting

Mentioning

273

Contrasting

Unclassified

Order By: Relevance

“…The cytokine IL-7 plays a fundamental role in homeostasis of the peripheral T-cell compartment [2][3][4]. IL-7 is limiting in replete conditions and is a key determinant of the T-cell compartment size, since total T-cell numbers in mice lacking one or other CD4 1 and CD8 1 subsets are near-identical to those in mice with both subsets [5][6][7]. Conversely, genetic over-expression of IL-7 [8,9] or its administration in vivo [10] increases T-cell numbers.…”

Section: Introductionmentioning

confidence: 99%

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

Pearson¹,

Silva²,

Saini³

et al. 2011

Eur J Immunol

View full text Add to dashboard Cite

The cytokine interleukin (IL)-7 is essential for Treg-cell homeostasis. It remains unclear, however, whether IL-7 regulates the homeostatic fitness of T cells quantitatively and, if so, by what mechanisms. We addressed this question by analysing T cells exposed to different levels of IL-7 signalling in vivo. Using TCR transgenic mice that conditionally express IL-7Ra, we show that T-cell longevity in the absence of survival cues is not a cellintrinsic property but rather a dynamic process of which IL-7 signalling is a key regulator. Naïve T cells deficient in IL-7Ra expression underwent rapid cell death within hours of in vitro culture. In contrast, the same T cells from lymphopenic hosts, in which IL-7 is nonlimiting, were able to survive in culture independently of growth factors for many days. Surprisingly, different levels of IL-7 signalling in vivo evoked distinct molecular mechanisms to regulate homeostatic fitness. When IL-7 was non-limiting, increased survival was associated with up-regulation of anti-apoptotic Bcl2 family members. In contrast, in T-cell replete conditions i.e. when IL-7 is limiting, we found evidence that IL-7 regulated T-cell fitness by distinct non-transcriptional mechanisms. Together, these data demonstrate a quantitative aspect to IL-7 signalling dependent on distinct molecular mechanisms.Key words: Fitness . Homeostasis . IL-7 . T cells Supporting Information available onlineIntroduction A commonly evoked concept in studies of lymphocyte homeostasis is that of cellular fitness. Whether a cell lives or dies in a particular context, such as effector cell transition to a memory state, or survival of recent thymic emigrants entering a replete peripheral compartment, is a function of its relative fitness [1]. The cytokine IL-7 plays a fundamental role in homeostasis of the peripheral T-cell compartment [2][3][4]. IL-7 is limiting in replete conditions and is a key determinant of the T-cell compartment size, since total T-cell numbers in mice lacking one or other CD4 1 and CD8 1 subsets are near-identical to those in mice with both subsets [5][6][7]. Conversely, genetic over-expression of 9] or its administration in vivo [10] increases T-cell numbers. It is likely, therefore, that IL-7 is a key determinant of homeostatic fitness. Lymphocytes are unlikely to have unfettered access to the multiple environmental cues required for their survival, but rather receive such signals on a sporadic basis. Consistent with this view, chemokines direct T cells to sites of IL-7 production within lymph nodes [11]. Thus, the homeostatic fitness of a T cell and consequently whether it lives or dies in a given homeostatic context may depend on how frequently it receives survival signals such as IL-7 and how long the cell can persist in the absence of such survival signalling.Ã These authors contributed equally to this work. 3656The mechanisms by which IL-7 maintains T-cell survival, and therefore regulate cellular fitness, have been the subject of numerous studies. Many of these have focused on the transc...

show abstract

Section: Introductionmentioning

confidence: 99%

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

Pearson¹,

Silva²,

Saini³

et al. 2011

Eur J Immunol

View full text Add to dashboard Cite

show abstract

“…Downregulation of CDS expression has also been noted in trans genie miee bearing antiself reeeptors l8 • Further, using a mutant mouse strain laeking eell-surfaee CDS expression, Fung-Leung et al 19 have shown that CDS is neeessary for the development of funetional alloreaetive or antigen-specifie class I, but not class 11, MHCrestrieted T eells.…”

mentioning

confidence: 99%

Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the α3 domain of MHC I molecules

Aldrich

Hammer

Jones-Youngblood

et al. 1991

Nature

View full text Add to dashboard Cite

As with studies on the Na + / K + pump24, early results on Na+ /Ca 2 + exchange appeared inconsistent with consecutive ion exchange models (see ref. 5 for review). Our work provides strong support for a consecutive Na +/Ca2+ exchange mechanism a nd should facilitate structure-function studies ofthe cloned Na+ /Ca2+ exchanger. The results of both ion jump experiments and steady-state I ~aCa measurements are inconsistent with Ca2+ translocation involving net negative cha rge movement 8• We conclude from our site-density estimates and I NaCa measurements that max imum exchanger turnover rates are about 5,000 S -I . As alread y proposed for the Na + / K + pumpl 2-17 and rod out er segment Na + / Ca2+ , K + excha nger 2 ,22, voltage-dependence must reside in the binding and release of extracellular Na+ or a closely associated occlusion/ deocclusion reaction. THE al and a2 domains of major histocompatibility complex (MHC) class I molecules function in the binding and presentation of foreign peptides to the T-cell antigen receptor and control both negative and positive selection of the T-ce)) repertoire l -3 , Although the a3 domain of class I is not involved in peptide binding, it does interact with the T-cell accessory molecule, CD8 (refs 4, 5). CD8 is important in the selection of T cells as anti-CD8 antibody injected into perinatal mice interfers with this process 6 • We previously used a hybrid class I molecule with the a 11 a2 domains from L d and the a3 domain from Q7 b and showed that this molecule 718 binds an Ld-restricted peptide but does not interact with CD8-dependent cytotoxic T lymphocytes 7• Expression of this molecule in transgenic mice faUs to negatively select a subpopulation of anti-L d cytotoxic T Iymphocytes. In addition, positive selection of virus-specific L d -restricted cytotoxic T lymphocytes does not occur. We conclude that besides the a1la2 domains of class I, the a3 domain plays an important part in both positive and negative selection of antigen-specific cells.To examine the role of the a3 domain of class I molecules in the responses of alloreactive and antigen-specific cytotoxic T Iymphocytes (CTL), we generated two transgenic mouse strains, C3H.L d and C3H.L Q 3, derived from C3H/ HeJ (H_2 k ) mi ce. C3H .L d express inta ct L d , whereas C3H.LQ3 ex press a n LU molecule whose a3 domain is switched with Q7 b . The Q7 b a 3 domain differs from LU at live residues and in addition has a unique three-amino-acid insert at positions 275-277 (ref. 8). We showed that this molecule (L Q3) binds the same viral peptide as L d but is not recognized by peptide-specific CD8-dependent CTL (ref. 7). Similar observations have been reported with a 3 mutant class I molecules not recognized by CD8-dependent CTL, the defect being due to an alteration in the binding site for C D8 (refs 4,5). 80th L d and L Q3 genes contain the same Qj .0

show abstract

“…Recent work in Drosophila demonstrated that apparently redundant enhancers are critical to maintaining expression in response to genetic and environmental stimuli (Frankel et al, 2010). Considering the importance of precisely controlled CD8 expression in lineage choice and cytotoxic T cell development (Fung-Leung et al, 1991;Sarafova et al, 2005), it is possible that this may also be the evolutionary driving force behind the development of multiple Cd8 locus enhancers. Another possibility is that seemingly overlapping Cd8 locus enhancers are important for the expression of Cd8a or Cd8b individually (Taniuchi et al, 2004).…”

Section: Epigenetic Regulation Of the Cd4 Locusmentioning

confidence: 99%

The Epigenetic Landscape of Lineage Choice: Lessons From the Heritability of Cd4 and Cd8 Expression

Gialitakis¹,

Sellars²,

Littman³

2011

Current Topics in Microbiology and Immunology

View full text Add to dashboard Cite

Developing αβ T cells choose between the helper and cytotoxic lineages, depending upon the specificity of their T cell receptors for MHC molecules. The expression of the CD4 co-receptor on helper cells and the CD8 co-receptor on cytotoxic cells is intimately linked to this decision, and their regulation at the transcriptional level has been the subject of intense study to better understand lineage choice. Indeed, as the fate of developing T cells is decided, the expression status of these genes is accordingly locked. Genetic models have revealed important transcriptional elements and the ability to manipulate these elements in the framework of development has added a new perspective on the temporal nature of their function and the epigenetic maintenance of gene expression. We examine here the novel insights into epigenetic mechanisms that have arisen through the study of these genes.

show abstract

CD8 is needed for development of cytotoxic T but not helper T cells

Cited by 498 publications

References 41 publications

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the α3 domain of MHC I molecules

The Epigenetic Landscape of Lineage Choice: Lessons From the Heritability of Cd4 and Cd8 Expression

Contact Info

Product

Resources

About