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Garvan Institute of Medical Research, Darlinghurst, Australia; and
Malaghan Institute of Medical Research, Wellington School of Medicine, Wellington, New Zealand
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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and protect against viral pathogens, whereas type 2
cells produce cytokines such as IL-4 and IL-5 and protect against large
extracellular parasites. Both CD4+ and CD8+ T
cells can be polarized into type 1 or type 2 cytokine-secreting cells,
suggesting that both populations play a regulatory role in immune
responses. In this study, we used high-density oligonucleotide arrays
to produce a comprehensive picture of gene expression in murine
CD4+ Th1 and Th2 cells, as well as CD8+ type 1
and type 2 T cells. Polarized type 1 and 2 cells transcribed mRNA for
an unexpectedly large number of genes, most of which were expressed in
a similar fashion between type 1 and type 2 cells. However, >100
differentially expressed genes were identified for both the
CD4+ and CD8+ type 1 and 2 subsets, many of
which have not been associated with T cell polarization. These genes
included cytokines, transcription factors, molecules involved in cell
migration, as well as genes with unknown function. The program for type
1 or type 2 polarization was similar for CD4+ and
CD8+ cells, since gene expression patterns were roughly the
same. The expression of select genes was confirmed using real-time PCR.
The identification of genes associated with T cell polarization may
give important insights into functional and phenotypic differences
between effector T cell subsets and their role in normal responses and
inflammatory disease. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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, which activates phagocytes and promotes protection against
intracellular pathogens. Type 2 (Th2) cells produce IL-4, IL-5, IL-13,
and IL-9 (2, 3), which together with IgE, eosinophils, and
basophils promote clearance of large extracellular parasites. Th1 or
Th2 responses are also important for inflammatory diseases. For
instance, allergic diseases such as asthma are thought to arise through
dysregulated type 2 responses, whereas many autoimmune diseases involve
type 1 responses (4, 5, 6). CD8+ T cells can also be polarized to effector subsets with distinct cytokine production profiles similar to those found in CD4+ T cells (7, 8). This polarization has been observed both in vitro and in vivo (9, 10, 11), and it is now likely that CD8+ T cells play an important regulatory role during immune responses. Both type 1 and type 2 CD8+ cells retain cytolytic activity (11), although relatively little is known about their regulatory roles in immune responses or pathological reactions.
Because of the importance of type 1 and type 2 T cells for immune responses, considerable effort has gone into defining the molecular differences between these two subsets. Transcription factors control type 1 and type 2 differentiation and include the type 2-associated factors GATA-3 (12), c-maf (13), and Stat6 (14, 15), as well as the type 1 factors T-bet (16), Stat4 (17), and IFN regulatory factor 1 (18, 19). What initiates transcription factor activity and type 1 or type 2 polarization is unclear, but may relate to the type and dose of Ag (20, 21, 22) or the nature of the APC (23, 24, 25). However, the ultimate determinant of T cell polarization is the cytokine milieu present at the time of T cell activation. IL-4 drives differentiation to type 2 cells, while IL-12 drives type 1 development (2, 3). The functional program of type 1 and 2 T lymphocytes requires these cells to home to different sites (26, 27, 28). Th1 cells preferentially express the chemokine receptors CCR5 and CXCR3, while Th2 cells preferentially express CCR3, CCR4, CCR8, and CRTh2 (reviewed in Ref. 1). Other cell surface molecules also distinguish type 1 and type 2 T cells, including ST2 (29), IL-18R (30), and P-selectin glycoprotein ligand 1 (28).
The comprehensive study of gene expression in cells has recently been made possible by the development of gene microarrays, including Affymetrix high-density oligonucleotide arrays. Teague et al. (31) analyzed changes in gene expression following naive T cell activation and found a surprisingly large number of genes expressed and regulated during T cell activation. A recent study that examined the differences in gene expression between human Th1 and Th2 cells identified genes involved in transcriptional regulation, apoptosis, and proteolysis, particularly for Th1 cells (32). In this study, we generated polarized populations of murine Th1 and Th2 cells as well as CD8+ T cells (Tc1)4 and Tc2 cells and analyzed gene expression using Affymetrix gene arrays. The pattern of gene expression in these polarized T cells provided detailed information not only on the differences between type 1 and type 2 cells, but also on the distinction between polarized CD4+ and CD8+ T cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Single-cell suspensions from spleen and lymph nodes of C57BL/6J mice (The Jackson Laboratory, Bar Harbor, ME) were washed in IMDM (Life Technologies, Auckland, New Zealand) containing 2 mM glutamine, 1% penicillin-streptomycin, 5 x 10-5 M 2-ME (all from Sigma, St. Louis, MO) without FCS, resuspended at 2 x 106cells/ml, and incubated for 2 h at 37°C to deplete macrophages. Anti-CD4 (5 µg/ml, GK1.5) or anti-CD8 (5 µg/ml, 2.43) was added to the suspension (1 x 106 cells/ml in incomplete medium) and cells were incubated for 30 min at 4°C under gentle rotation. This was followed by an identical incubation with streptavidin-conjugated Dynabeads (Dynal Biotech, Oslo, Norway) added at five beads per cell. After magnetic enrichment, cells were 90–100% CD4+ or CD8+ by FACS staining.
Purified T cells (1 x 106/ml) were grown in 6-well plates (Falcon; BD Biosciences, Mountain View, CA) coated with Armenian (5 µg/ml) and Syrian (2 µg/ml) anti-hamster Abs (both from BD PharMingen, San Diego, CA) and recoated with anti-CD3 (2C11). 10 U/ml IL-2 (human recombinant IL-2L6), 10 ng/ml IL-6, and soluble anti-CD28 (1:50 final concentration of 37.51 hybridoma supernatant) were added to Tc1 cultures. For Th1, Th2, and Tc2 cell generation, conditions were identical to those for Tc1 generation; however, 10 ng/ml IL-12 (BD PharMingen) was added to Th1 cultures and IL-4 (produced in stationary cultures of a mouse IL-4-producing cell line) was added to Th2 and Tc2 cultures at 2000 U/ml. Cultures were maintained for 5 days, with replacement anti-CD28 and cytokines on days 2–4. On day 5, cells were removed from the plates and transferred to uncoated 6-well plates with 100 U/ml IL-2 for 48 h (IL-2 was replaced after 24 h). After which cells were restimulated with anti-CD3 without the cytokines for 24 h and harvested.
Real-time PCR to monitor gene expression
Total RNA was isolated from cells using the RNeasy Total RNA
Isolation kit (Qiagen, Chatsworth, CA) as per the manufacturer’s
instructions. RNA (2 µg per reaction) was reverse transcribed using
avian myeloblastosis virus Reverse transcriptase (Promega, Madison, WI)
at 42°C for 70 min in the presence of 250 µM dNTPs, avian
myeloblastosis reverse transcription 5x reaction buffer (250 mM
Tris-HCl, 250 mM KCl, 50 mM MgCl2, 50 mM DTT, and
2.5 mM spermidine; Promega) and 1 µM
oligo-p(dT)15 primer (Roche Molecular
Biochemicals, Sydney, Australia). Following cDNA synthesis, 2 µl of
cDNA template was used for each PCR. Real-time PCR were conducted using
a Light Cycler-FastStart DNA Master SYBR Green I kit (Roche Molecular
Biochemicals) according to the manufacturer’s specifications using 3
mM MgCl2 and 1 µM primers. Primers used for the
analysis of cytokine expression are as in the study by Overbergh et al.
(33). Each gene was normalized to a housekeeping gene
(
-actin) before fold change was calculated (using crossing point
values) to account for variations between different samples. Following
identification of the differentially expressed genes, the expression of
selected genes was analyzed by real-time PCR as described above using
primers designed for the particular genes using MacVector software
(version 6.5.3; Oxford Molecular Group).
Preparation of cRNA and GeneChip hybridization
cDNA was specifically transcribed from the poly(A) mRNA using a poly(T) nucleotide primer containing a T7 RNA polymerase promoter (GeneWorks, Adelaide, Australia). Biotinylated antisense target cRNA was subsequently synthesized by in vitro transcription using the Enzo BioArray High-Yield RNA Transcript Labeling kit. The biotin-labeled target cRNA was then fragmented and used to prepare a hybridization mixture, which included probe array controls and blocking agents. This mixture was initially hybridized to test arrays to evaluate the quality of the cRNA and then to Mu11K (11,000 murine genes and expressed sequence tag (EST) clusters) arrays for expression analysis. Washing and staining of the hybridized probe array were performed by an automated fluidics station according to the manufacturer’s protocols. The stained array was then scanned and the resultant image captured as a data image file.
Data analysis
From data image files, gene transcript levels were determined using algorithms in the GeneChip Analysis Suit software (Affymetrix). The expression levels of all genes on the array set were compared between type 1 and type 2 cells, with differences of 2-fold or larger likely to reflect significant changes in gene expression. Genes that showed a change of 2-fold or greater in at least two separate experiments were considered as differentially expressed. Each probe was assigned a call of present (expressed) or absent (not expressed) using Affymetrix decision matrix. GenBank, BLAST, and Celera databases were regularly monitored for the presence of full-length genes corresponding to EST probes. A small percentage of probes on Mu11K array set was found by Affymetrix to be made using mouse sequences that were input into the databases with ambiguous directionality assignments. The results presented in this paper are only minimally affected by these ambiguities.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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). We performed polarization using
procedures which in our laboratory have been shown to generate highly
distinctive cytokine-secreting subsets. Thus, the Th2 cells that we
generated showed a much higher expression of RNA transcripts for IL-4,
IL-5, and IL-10, whereas Th1 cells expressed higher levels of
transcripts for IL-2 and IFN- as expected (2, 3). Other genes such as IL-13 showed expression patterns
consistent with published reports, indicating that our polarization
protocol was yielding well-differentiated Th1 and Th2 cells. The
cytokine expression profiles in CD8+ cells
followed a similar pattern; IFN- was expressed at a higher level in
Tc1 cells, while expression of IL-4, IL-5, IL-10, and IL-13 was much
higher in Tc2 cells similar to previous reports (8, 11).
Expression of type 2 cytokines was particularly strong, for both
CD4+ and CD8+ cells, and
our experimental protocol may favor high type 2 cytokine expression
compared with type 1 cytokine expression. For
CD8+ cells, IFN- has been reported to be
expressed abundantly in type 1 cells, but also to some extent in type 2
cells (10, 34). In addition to the RNA studies, we also
showed, using cytokine ELISAs, that our polarized cells had
differentiated to type 1 and type 2 cytokine-producing phenotypes (data
not shown). For instance, Tc2 cells produced >35-fold more IL-4 and
IL-5 protein than Tc1 cells.
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). Of 11,000
full-length genes and ESTs analyzed, we found that 
60% of all
probes for both CD4+ and
CD8+ T cells were expressed (according to a call
made for each probe using an Affymetrix decision matrix) in either type
1 or type 2 cells (Fig. 2, insets). A previous study also
showed a high degree of gene expression in naive and activated T cells
(31). The majority of genes expressed by T cells did not
show biased expression under type 1- or type 2-polarizing conditions,
suggesting that most gene products perform housekeeping processes or
functions common to both type 1 and type 2 T cells. Nevertheless, we
found a number of genes expressed preferentially in either type 1 or
type 2 T cells.
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. These genes could be classified into a
number of functional categories. A large number of cytokines and growth
factors were preferentially expressed by either type 1 or type 2 cells
(Fig. 3i). We had a high degree of confidence in our array
results, since expected patterns of cytokine gene expression were
observed. For instance, IL-4, IL-5, IL-10, IL-6, IL-3, IL-13, GM-CSF,
IL-2, lymphotoxin 
, and IFN- were expressed as expected. We also
noted that type 2 cells expressed higher levels of stromal cell-derived
factor 3, as well as the epidermal growth factor-like growth factor
amphiregulin. Both of these factors have not been previously associated
with T cell functions. Furthermore, according to our microarray
results, Tc2 cells for the most part resembled Th2 cells in their
cytokine profile (see below). IL receptors were also differentially
expressed on type 1 and type 2 cells. For instance, IL-1R-related
protein 1, which has recently been shown to be a component of the
IL-18R (35, 36, 37), was preferentially expressed in both Th1
and Tc1 cells. Preferential expression of this molecule by Th1 cells
was first shown by Xu et al. (30). We have noted that
another member of the IL-1R-like family, IL-1R type II was expressed at
a higher level in Tc2 cells.
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ii), some of which (GATA3, c-maf, and Stat4)
have been well characterized (12, 13, 17, 38, 39). In
addition, several transcription factors that have not been associated
with T cell polarization were also identified, including
c-fos and mouse HLF 1-like factor for type 2 cells and
early B cell factor for type 1 T cells. It is conceivable that these
various transcription factors might control individual cytokine gene
expression. For instance, c-maf controls IL-4 production
(13, 39), whereas T-bet has been shown to be linked with
IFN- production (16).
Two members of the TNF receptor-associated factor (TRAF) family were
found to be differentially expressed in type 1 and type 2 cells. TRAF4
was expressed at a higher level in type 1 cells while TRAF5 was
preferentially expressed in type 2 cells (Fig. 3vi). Members
of this family serve as adapter proteins that mediate cytokine
signaling, in particular they seem to play a role in signal
transduction from TNF receptor and Toll/IL-1R families, resulting in
activation of transcription factors NF-
B and AP-1
(40).
A consistent finding by various groups, including our own, is the
differential expression of cell migration-related molecules on type 1
and type 2 cells (26, 27). As shown in Fig. 3Aiii, Th2 cells expressed higher levels of transcripts for
CCR1, 7 integrin, and CXCR4, while Th1 cells expressed
higher levels of 4 integrin. The expression of CCR1 on
polarized T cells has been the subject of some debate because it was
previously considered to be Th1 specific but recently there has been
emerging evidence to suggest otherwise (27). Higher levels
of CCR1 transcript were expressed by both CD4+
and CD8+ type 2 T cells. A recent study showed
that CCR1-deficient mice have significantly lower levels of the Th2
cytokines IL-4 and IL-13 in an allergic airway model (41).
Th2 cells also produced chemokines such as I-309 (the ligand of a
Th2-associated receptor CCR8 (42, 43). Our GeneChip
experiments failed to confirm preferential expression of several other
chemokine receptors. In particular, type 2 chemokine receptor CCR3 was
not differentially expressed in most of the experiments, nevertheless,
we noted preferential expression of CCR4 by type 2 cells in one of the
experiments. Type 1 chemokine receptor CCR5 was not differentially
expressed in CD8+ cells but was slightly (2-fold)
overexpressed by Th2 cells. This deviation from the expected chemokine
receptor profile could be due to the fact that the expression of some
chemokine receptors varies depending on cytokine stimulation and other
factors (44). The receptors CXCR3 and CRTh2 were not
included in the array set.
Interestingly, our GeneChip experiments identified differential
expression of several granzymes. For instance, Th1 cells expressed
higher levels of granzyme C compared with Th2 cells (Fig. 3Aiv), while Tc2 cells expressed elevated levels of
granzymes D, E, and F (Fig. 3Biv). Granzymes are a family of
serine proteases which are found in cytotoxic lymphocyte granules.
Although granzymes A and B have been shown to be involved in cytolysis,
the biological functions of granzymes C–F are yet to be identified
(45). Several studies have compared cytolytic abilities of
Tc1 and Tc2 cells but the results have been inconclusive (46, 47). Tc1 cells may be more efficient at clearing some viral
infections than Tc2 cells, although this could relate to different
migration properties of the two subsets (48, 49).
Expression of select genes identified as differentially expressed by
microarray analysis was confirmed by real-time PCR (Fig. 4). Although there were differences in
the fold-change values detected by the two methods, real-time PCR
results correlated well with the differential gene expression data
produced using Affymetrix GeneChips. This gave us confidence that the
gene expression data derived from the gene arrays was reliable. In
addition to the differentially expressed full-length genes, we also
identified a number of differentially expressed ESTs (Table I). For some of the ESTs, full-length
genes have now been identified. Among the differentially expressed ESTs
for which the full-length genes are already known, we noted
preferential expression by Th2 and Tc2 cells of cytochrome P450 side
chain cleavage enzyme 11a1 and aldoketoreductase , while both Th1
and Tc1 cells expressed higher levels of transcripts homologous to Jun
dimerization protein gene. The significance of these genes in T cell
polarization and function needs to be addressed in additional
studies.
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). This indicates a degree of
similarity in the genetic program leading to T cell polarization. This
was expected since similar factors induce polarization of both Th and T
cytotoxic cells into type 1 and type 2 subsets, and roughly similar
cytokine-producing phenotypes are created. Despite some similarity in
gene expression, there were also some differences since many of the
genes that were differentially expressed in CD8+
T cells were not in CD4+ T cells and vice versa
(Fig. 3). These genes could be responsible for the distinct properties
of the Th and T cytotoxic subsets. In addition, a small number of genes
differentially expressed by both showed the opposite patterns of
expression.
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Acknowledgments |
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Footnotes |
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2 T.C. and R.A.K. contributed equally to this manuscript.
3 Address correspondence and reprint requests to Dr. Charles R. Mackay, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. E-mail address: c.mackay{at}garvan.org.au
4 Abbreviations used in this paper: Tc, CD8+ T cells; TRAF, TNF receptor-associated factor, EST, expressed sequence tag.
Received for publication May 14, 2001. Accepted for publication July 16, 2001.
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and 
) indicate that the transcript is present at
a higher level in type 2 cells, while negative values indicate that the
transcript is more abundant in type 1 cells. Corresponding fold-change
values for CD4+ (A) and CD8+
(B) T cells as determined by GeneChip (