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The Journal of Immunology, 1999, 162: 5053-5057.
Copyright © 1999 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Stable Epigenetic Inheritance of Regional IFN-{gamma} Promoter Demethylation in CD44highCD8+ T Lymphocytes1

David R. Fitzpatrick2, Kym M. Shirley and Anne Kelso

Leukocyte Biology Unit of the Queensland Institute of Medical Research and the Joint Transplantation Biology Program of the University of Queensland, Brisbane, Australia


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Genomic DNA methylation patterns influence the development and maintenance of function during cellular differentiation. Methylation of regulatory sequences can have long-lasting effects on gene expression if inherited in an epigenetic manner. Recent work suggests that DNA methylation has a regulatory role in differential cytokine gene expression in primary T lymphocytes. Here we show, by clonal lineage analysis, that methylation patterns in the IFN-{gamma} promoter exhibit long term faithful inheritance in CD44highCD8+ T cells and their progeny, through 16 cell divisions and a clonal expansion of 5 orders of magnitude. Moreover, the demethylated IFN-{gamma} promoter is faithfully inherited following the withdrawal of T cell stimulation and the loss of detectable IFN-{gamma} mRNA, consistent with passive rather than active maintenance mechanisms. This represents a form of stable cellular memory, of defined epigenetic characteristics, that may contribute to the maintenance of T cell cytokine expression patterns and T cell memory.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Methylation of genomic DNA cytosines can regulate gene expression and CpG methylation status can be inherited, thus transmitting functions through cell division epigenetically (1, 2, 3). Roles for methylation in gene expression in lymphocytes have not been widely studied (1). Differential IFN-{gamma} gene methylation is closely associated with IFN-{gamma} expression in T cells: the gene is demethylated in T cells expressing IFN-{gamma} whereas methylation is accompanied by lack of expression (4, 5, 6, 7, 8). This holds for natural methylation differences between T cells and for artificial differences induced by methyltransferase inhibitors. IFN-{gamma} promoter methylation can inhibit transcription factor binding (4, 9) and can be inherited, at least in the short term, in subclones of CD44high (previously activated or memory/effector) CD8+ T cells (8). This suggests an epigenetic role for methylation in regulation of T cell IFN-{gamma} expression, but questions remain about the stability of methylation patterns.

Here we show that regional demethylation of the IFN-{gamma} promoter can be a long term, stable feature of CD44highCD8+ T cells and their progeny, even without TCR stimulation or IFN-{gamma} expression. This is the first such report for any endogenous inducible gene in clonal lineages of primary cells and suggests a molecular basis for memory in individual T cells.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Lymphocyte preparation and culture

CD44highCD8+ T cells were isolated from C57BL/6 mouse lymph nodes by sorting (FACS Vantage, Becton Dickinson, Sunnyvale, CA) for the highest 15% of the CD44 profile of the CD8+ cells. Sorted cells (>=95% pure) were deposited automatically and singly into Terasaki plates coated with three mAb specific for CD3{epsilon}, LFA-1, and CD8 (8, 10). Supplemented DMEM was added to attain final levels of 15% FCS and 600 IU/ml rIL-2 (Cetus, Emeryville, CA). Cell deposition and growth were monitored by microscopy, and subcloning was performed by micromanipulation, initially after 4 days of stimulation. On day 7, the primary clones and some subclones were harvested and a second micromanipulation was conducted on other subclones to create tertiary cultures that were harvested on day 10. Stimulation was maintained for some subclones but withdrawn for others by seeding into uncoated plates for growth in IL-2 alone. This approach created families of clones where related progeny had been exposed to varying stimulation conditions (Fig. 1Go).



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  		FIGURE 1. Clonal lineage strategy. Single murine CD44highCD8+ T cells were sorted into Terasaki plates and stimulated with IL-2 and mAb specific for CD3{epsilon}, LFA-1, and CD8. After 4 days, the parent clones were subcloned by micromanipulation into cultures with either solid-phase mAb and IL-2 ({circ}) for maintained stimulation, or IL-2 alone (•) for short term, temporary, or long term withdrawal of stimulation. Three days later, the parent clones and some of the subclones were harvested, and a second micromanipulation was similarly conducted on the remaining subclones. All of the progeny subclones were then harvested on day 10. This approach creates families of clones where related progeny have been exposed to varying conditions of stimulation during a clonal expansion of 3–5 orders of magnitude.

 
Bisulfite genomic DNA sequencing

Nuclear DNA was extracted and bisulfite modified as detailed (8), deaminating nonmethylated cytosines but leaving methylated cytosines intact and amenable to positive display via PCR and DNA sequencing. Each strand of the IFN-{gamma} promoter was amplified in a two-round seminested PCR, with >=20% of each set of reactions as negative controls. PCR products were purified and sequenced directly using dye terminator reagents, 2–3 primers and automated analysis (PE Biosystems, Burwood, Victoria, Australia). This approach comprehensively assesses the methylation status of all CpG sites on both strands of the IFN-{gamma} promoter for 350 bp around the transcription start site. Direct sequencing displays the predominant methylation status of heterogeneous populations of molecules and allows semiquantitation of intermediate states between 25 and 75% by scoring coincident C and T peaks (8).

RNA isolation, cDNA synthesis, and quantitative competitive PCR (QCPCR)3

Cytoplasmic RNA was isolated by hypotonic lysis in the presence of RNase inhibitors and reverse transcribed into cDNA (8, 11). QCPCR was conducted using Red Hot polymerase (Advanced Biotechnologies, Leatherhead, Surrey, U.K.) with the supplied reaction buffer, 2 mM MgCl2, 200 µM dNTPs, 10 µM primer IFNGin5' (11), 10 µM biotinylated primer IFNGin3', 1 µl of T cell cDNA, and 2 µl of competitor plasmid dilutions. Competitor plasmids with 82 bp deletions in the IFN-{gamma} or CD3{epsilon} sequences had been constructed, purified, and serially diluted (8). Each cDNA was tested against fivefold competitor dilutions over 7 orders of magnitude. To standardize extraction and cDNA synthesis variations, QCPCRs for the stimulus-resistant CD3{epsilon} mRNA were also conducted using the primers CD3Ein5' and biotinylated CD3Ein3' (11). PCR products were captured on streptavidin-coated plates, hybridized with specific FITC-labeled probes, and quantitated with an alkaline phosphatase-conjugated anti-fluorescein Ab and a color substrate (8).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Long term heritability of IFN-{gamma} promoter methylation patterns in CD44highCD8+ T cells

In our previous study of IFN-{gamma} gene methylation heritability (8), single CD8+ T cells were stimulated using solid phase mAb and IL-2, and the resultant clones (120–250 cells) were subcloned after 4 days. Parent clones and subclones were then harvested after 2–3 more days of stimulation, thus allowing 2–6 cell divisions and clonal expansion of 4- to 64-fold. Herein, we extended this strategy to cover 10 days, two micromanipulation steps, and more cell divisions (Fig. 1Go). Microscopic assessment confirmed that the subclones had doubled every 9–12 h, after lag phases of 0–24 h, and by the end of the experiment had divided 10–16 times from the first micromanipulation, representing a clonal expansion of 3–5 orders of magnitude.

For each subclone, the methylation status of every cytosine in the coding and noncoding strands of the IFN-{gamma} promoter was analyzed by bisulfite DNA sequencing. As validation, 1) all contamination controls were negative, 2) >99% of non-CpG cytosines exhibited bisulfite conversion, 3) sequencing results were reproducible for 2–3 reactions on each PCR product, and 4) the status of matched CpG sites in the coding and noncoding strands, derived from amplifications of separate sample aliquots, was symmetrical in >85% of cases. In parallel, IFN-{gamma} mRNA was measured by QCPCR and standardized to similarly quantitated CD3{epsilon} mRNA levels. The QCPCR sensitivity was low, at 20–100 input molecules, and the reproducibility between assays was high, with SD <15% of the means (8). In these ways, IFN-{gamma} promoter methylation and mRNA expression were simultaneously assessed in families of primary CD44high T cell clones.

In the parent clones (Fig. 2Go, clones A0, B0, C0), 7 contiguous IFN-{gamma} promoter CpG sites, from -205 to +17 relative to the transcription start, were usually symmetrically demethylated, as expected (8). Conversely, the +97 site was usually symmetrically methylated, as was the +120 site (data not shown), suggesting a 3' boundary for regional demethylation of the IFN-{gamma} promoter, {approx}100 bp down from transcription initiation. Others have found demethylated sites 1–4 kb further downstream in some T cells (4, 5, 6), which may reflect cell or stimulation differences, or patchwork demethylation of the gene.



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  		FIGURE 2. Long term heritability of IFN-{gamma} promoter methylation patterns in families of CD8+ T cells under continuous stimulation. CpG sites in the IFN-{gamma} promoter are shown and numbered relative to the transcription start site (arrow). Methylation patterns in the IFN-{gamma} promoter are shown for members of four families of T cell clones. Each member has a code comprising the family (upper case letter), the generation of the clone or subclone (0 = parent, 1 = first micromanipulation subclone, 2 = second micromanipulation subclone), and an individual discriminator (lower case letter). Families A–C were derived from CD44highCD8+ T cells, whereas family D was derived from a CD44lowCD8+ T cell. Second micromanipulation subclones were derived from the subclones A1c, B1c, and C1b. Methylation status of each CpG site of the coding (upper line of symbols) and noncoding (lower line of symbols) strands of the IFN-{gamma} promoter are scored as shown. IFN-{gamma} mRNA levels measured in parallel are shown at the right and expressed in CD3{epsilon} units. The results are representative of 91 parent and progeny clones, from 16 families analyzed after 1 micromanipulation and 5 families analyzed after 2 micromanipulations.

 
Fig. 2Go also shows that, under maintained stimulation, regional demethylation of the IFN-{gamma} promoter in the parent clones was faithfully inherited by all of their progeny after both the first and second micromanipulations. Thus, IFN-{gamma} promoter methylation patterns can be preserved in CD44highCD8+ T cells during a prolonged clonal expansion of up to 16 divisions and 5 orders of magnitude. This contrasts with the progeny of CD44lowCD8+ T cells (Fig. 2Go, family D) where a less demethylated pattern is variably inherited (8).

Stable heritability of IFN-{gamma} promoter methylation patterns in CD44highCD8+ T cells

The above results leave open the possibilities that IFN-{gamma} promoter demethylation is maintained by TCR stimulation or mRNA transcription. The former is consistent with proposed demethylation mechanisms (1). The latter is supported by the IFN-{gamma} mRNA expression in all of the subclones (Fig. 2Go). We therefore tested whether withdrawing TCR stimulation, while maintaining cell division by culture in IL-2 alone (Fig. 1Go), would alter IFN-{gamma} promoter methylation.

Remarkably, a regionally demethylated IFN-{gamma} promoter was faithfully inherited in all of the progeny of CD44highCD8+ T cells, even after stimulation withdrawal (Fig. 3Go). There were no significant methylation pattern differences, regardless of the order or duration of the altered conditions. This contrasted with the IFN-{gamma} mRNA data where growth in IL-2 alone often reduced IFN-{gamma} mRNA to undetectable levels (Fig. 3Go, subclones A2e, A2h, A2i, C2c, C2f, and C2g), while stimulation maintained or recalled IFN-{gamma} mRNA expression (Fig. 3Go, subclones A2f, A2g, B2e, B2f, C2d, and C2e). Some subclones expressed low levels of IFN-{gamma} mRNA even after prolonged culture in IL-2 alone (e.g., Fig. 3Go, subclones B2g and B2h). Interestingly, this was characteristic of individual families (Fig. 3Go and data not shown). Additionally, some parent and progeny clones expressed low IFN-{gamma} mRNA levels despite continued stimulation. Some of these reductions may be artifactual postmicromanipulation (Fig. 3Go, subclones B1c and C1b), but others may reflect that the subcloning strategy was optimized for extended cell division rather than synchronous mRNA expression. Thus, IFN-{gamma} mRNA levels may have been affected by clonal variations, the subcloning time course, and deliberately altered culture conditions.



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  		FIGURE 3. Stable inheritance of IFN-{gamma} promoter methylation patterns in families of CD8+CD44high T cells after short term, temporary, or long term withdrawal of stimulation. Families of clones were derived and cultured as described in Fig. 1Go. Data from clones grown under maintained stimulation are enclosed by open boxes, and data from clones cultured in IL-2 alone are enclosed by shaded boxes. Subclone identification codes are at the left of each box, methylation data are shown as two rows of symbols, and IFN-{gamma} mRNA levels are at the right of each box as described in the legend to Fig. 2Go. These results are representative of 5 independent families and 53 progeny clones additional to those shown in Fig. 2Go.

 
These results suggest that a regionally demethylated IFN-{gamma} promoter can be stably inherited and need not be maintained by continuous TCR stimulation or IFN-{gamma} mRNA expression. A role for IL-2 and its receptor complex in maintaining demethylation via low level IFN-{gamma} mRNA expression in some T cells remains possible (12). This potential mechanism merits further study, but it is unlikely to be applicable to all CD44high T cells, as shown in Fig. 3Go and as reported for some memory/effector T cells analyzed ex vivo from normal individuals, without stimulation or IL-2 exposure (5). The corollary that active processes may yet be required for de novo methylation (7) should also be addressed.

Evidence for methylation inheritance has come mostly from cell lines transfected with exogenous DNA (2). Variable fidelity has been reported for endogenous genes in primary cells, but often only at a single CpG site or in a few clones with unknown gene expression levels (13). This is the first demonstration of stable inheritance of a demethylated endogenous inducible gene in clonal lineages of primary cells.

Stable cellular memory in T cells and immunological memory

Augmented IFN-{gamma} production is characteristic of memory/effector T cells (14). The data above suggest how such an acquired inducible function can be transmitted in clonal lineages of T cells. Specifically, we show that the inheritance of epigenetic regulatory methylation patterns in CD44high T cells can exhibit the qualities of long-lasting and stable memory. Immunological memory is likely to involve many features of many cells: some models emphasize in vivo population phenomena (15, 16, 17); whereas others emphasize acquired functions of individual cells (14, 18, 19). A key characteristic of a cell involved in a recall response may be the transmission of acquired functions to its progeny. Attempts have been made to redefine naive and memory B cells on a genetic basis (the ability of their progeny to mutate) (20). We suggest that a similar definition can be considered for T cells, but on an epigenetic basis (the ability to stably transmit a pattern of DNA methylation that regulates effector gene expression).


   Acknowledgments
 
We thank Grace Chojnowski, Macky Edmundson, and Helle Bielefeldt-Ohmann for invaluable help.


   Footnotes
 
1 This work was supported by the National Health and Medical Research Council, the Queensland Cancer Fund, and the Queensland Institute of Medical Research Trust. Back

2 Address correspondence and reprint requests to Dr. David Fitzpatrick, Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, QLD 4029, Australia. E-mail address: Back

3 Abbreviation used in this paper: QCPCR, quantitative competitive PCR. Back

Received for publication January 4, 1999. Accepted for publication March 3, 1999.


   References
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 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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