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CUTTING EDGE |
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
| Abstract |
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| Introduction |
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, and IL-2R
deficient (/) mice all die early in life of severe lymphoproliferation and autoimmune disease (2, 3, 4) and IL-2 and IL-2R
/ mice have few or no CD4+CD25+ cells. Furthermore, while STAT5-deficient mice have very few CD4+CD25+ cells, mice transgenic for the active form of STAT5 possess a greater frequency of these cells (5, 6), thus confirming the requirement for IL-2 signaling in CD4+CD25+ T cell homeostasis. Recent studies suggest that the IL-2/IL-2R pathway is important for CD4+CD25+ T cells at several stages. CD4+CD25+ cell numbers are restored and the induction of autoimmune disease is prevented when an IL-2R
transgene is expressed solely in the thymus of IL-2R
/ mice, indicating that an intact IL-2/IL-2R pathway is required in the thymus for generation of CD4+CD25+ cells (7). IL-2 signaling in the periphery is also required for the expansion of CD4+CD25+ cells. Although the transfer of wild-type CD4+CD25+ cells to IL-2R
/ mice resulted in a marked expansion of the transferred cells and prevented the induction of disease, the transfer of wild-type CD4+CD25+ cells into IL-2/ mice did not lead to engraftment or expansion of CD4+CD25+ cells and did not prevent autoimmune disease or death, suggesting that IL-2 is needed for the expansion and/or homeostasis of CD4+CD25+ cells. Similarly, Furtado et al. (8) demonstrated that CD4+ T cells from IL-2/ mice protected mice from spontaneous experimental autoimmune encephalomyelitis, while CD4+ T cells from CD25/ mice did not; thus, IL-2 derived from the recipient drove expansion of IL-2/ cells, but was unable to drive the expansion of CD4+CD25/ cells. Other factors may also control the homeostasis of CD4+CD25+ T cells, as mice with defects in delivery or receipt of costimulation (CD28/, CD80/CD86/, CD40/), may have quantitative or qualitative defects in CD4+CD25+-mediated functions (9, 10). Some of these defects appear to be independent of IL-2 (11). Although IL-2 and its receptor clearly play a critical role in the homeostasis of CD4+CD25+ T cells in vivo, the potential contribution of IL-2 to their suppressive function remains elusive. Indeed, the molecular basis for suppression of T cell activation by CD4+CD25+ T cells in vitro is inhibition of IL-2 gene transcription in the CD4+CD25 responder T cells. Furthermore, addition of IL-2 or the enhancement of costimulation by the addition of anti-CD28 are thought to break the anergic state of the CD4+CD25+ T cells and abrogate their suppressive function. One of the major problems with interpretation of this data is that T cell proliferation has been used as the major readout of suppression and both CD4+CD25+ and CD4+CD25 cells proliferate under these conditions. In this study, we have used a quantitative assay of suppression of IL-2 transcription to re-evaluate the role of IL-2 in the suppressor function of CD4+CD25+ T cells. We demonstrate that transcription of IL-2 mRNA remains fully suppressed in the presence of high concentrations of exogenous IL-2 and in the presence of proliferation of both the CD4+CD25+ suppressors and the CD4+CD25 responders. In contrast, the addition of anti-CD28 to the suppression assay results in abrogation of suppression as transcription of IL-2 mRNA is partially restored. Thus, abrogation of the anergic state of CD4+CD25+ cells does not break suppression, as previously thought. Most importantly, the addition of anti-IL-2 completely abrogates the suppressive effects of CD4+CD25+ T cells on IL-2 mRNA transcription and demonstrates that IL-2 is not only required for the generation and peripheral maintenance of CD4+CD25+ cells, but is also required for the acquisition of suppressor function. The implications of these findings for the in vivo effects of CD4+CD25+ T cells are discussed.
| Materials and Methods |
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Female BALB/c mice were obtained from the National Cancer Institute (Frederick, MD). BALB/c Thy1.1 congenic mice were obtained from R. A. Seder (National Institutes of Health, Bethesda, MD) and were bred and maintained in National Institute of Allergy and Infectious Diseases/National Institutes of Health animal facilities.
Media, reagents, and Abs
Cells were grown in RPMI 1640 (Biofluids, Rockville, MD) supplemented with 10% heat-inactivated FCS, penicillin (100 µg/ml), streptomycin (100 µg/ml), 2 mM L-glutamine, 10 mM HEPES, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate (all Biofluids), and 50 µM 2-ME (Sigma-Aldrich, St. Louis, MO). Biotin-anti-CD25 (7D4), PE-streptavidin, anti-CD3 (2C11), anti-CD28, and anti-IL-2 (S4B6) were purchased from BD PharMingen (San Diego, CA). Anti-CD90 (Thy1.2), anti-CD8, and anti-PE magnetic beads were purchased from Miltenyi Biotec (Auburn, CA). Human rIL-2 was obtained from the Preclinical Repository of the Biological Resources Branch, National Cancer Institute. IL-4 was purchased from R&D Systems (Minneapolis, MN). Flow cytometry analysis to assess cell purity was performed using CellQuest software (BD PharMingen).
Cell purification
CD4+CD25 and CD4+CD25+ cells were purified as previously reported (12), unless stated otherwise. Purity ranged from 95 to 98%. T-depleted spleen cells (T
S) were used as APC and were prepared by lysing erythrocytes with ACK lysis buffer (Biofluids), followed by depletion of CD90+ cells on an autoMACS (Miltenyi Biotec). APC were irradiated with 3000R.
Proliferation assays
CD4+CD25 cells (5 x 104), CD4+CD25+ cells (5 x 104), or CD4+CD25 cells (5 x 104) cocultured with CD4+CD25+ cells (2.5 x 104) were cultured in 96-well plates (0.2 ml) with APC (5 x 104) and 0.25 µg/ml anti-CD3 for 72 h at 37°C/7% CO2 in the presence of any indicated reagents. IL-2 was used at 50 U/ml, IL-4 at 20 ng/ml, and anti-CD28 at 0.5 µg/ml. Cultures were pulsed with [3H]TdR for the last 6 h of culture. All experiments were set up in triplicate.
CFSE labeling
Thy 1.1 CD4+CD25 or Thy 1.2 CD4+CD25+ cells were labeled with 2 µM CFSE for 8 min at room temperature. Cells were set up as in standard 96-well proliferation assays in triplicate. At 70 h, the triplicates were pooled and analyzed by flow cytometry.
Quantitative IL-2 mRNA analysis
CD4+CD25 cells, CD4+CD25+ cells, or CD4+CD25 cells cocultured with CD4+CD25+ cells were cultured with APC and 0.25 µg/ml anti-CD3 in the presence of indicated reagents for 44 h. Reactions were set up in 96-well plates as for the proliferation assays and the contents of one plate (
5 x 106 cells) pooled at 44 h. Total RNA was prepared with an RNeasy kit (Qiagen, Valencia, CA) during which on-column DNase I treatment (Qiagen) was performed. cDNA was made using Superscript II (Invitrogen, Carlsbad, CA) with random primers (Invitrogen). Primers and FAM-labeled probe for IL-2 and IL-4 were purchased from Applied Biosystems (Foster City, CA). As an internal control for normalization, 18S ribosomal RNA (rRNA) (Applied Biosystems) was used. Standard curves were set up for IL-2 and 18S rRNA. For each sample, the results of IL-2 gene expression were normalized relative to its 18s rRNA. The IL-2 gene expression of normalized unstimulated CD4+CD25 cells was given an arbitrary value of 1.0 and the remaining samples were plotted relative to that value. All PCRs were performed in triplicate with a TaqMan Universal PCR Master Mix (Applied Biosystems). An ABI Prism 7700 Sequence Detection System (Applied Biosystems) was used for 40 cycles of PCR. Each experiment was performed at least three times and a representative experiment is shown.
| Results |
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As previously shown, coculture of CD4+CD25+ and CD4+CD25 T cells results in inhibition of the proliferative response of CD4+CD25 cells, which is reversed to varying extents by the addition of IL-2, IL-4, or anti-CD28 (Fig. 1A) (13, 14, 15). As purified CD4+CD25+ T cells proliferate when stimulated with anti-CD3 and IL-2 (13, 14), it has been assumed that when the in vitro nonresponsive state of the CD4+CD25+ cells is broken, their suppressive function is abolished. However, it is possible that CD4+CD25+ cells retain their suppressive function, and proliferation of both the CD4+CD25+ and CD4+CD25 populations is driven by the addition of the exogenous agents. To address this possibility, we used CFSE dilution experiments to independently examine the proliferation of CD4+CD25 and CD4+CD25+ cells under coculture conditions. As shown in Fig. 1B, CD4+CD25 cells manifested a significant proliferative response which was enhanced by the addition of IL-2, IL-4, and anti-CD28. CD4+CD25+ cells cultured with anti-CD3 alone or with anti-CD3/CD28 did not divide significantly, but as was observed in the [3H]TdR uptake assays, proliferated vigorously when stimulated with anti-CD3 and IL-2 or IL-4. In the cocultures, CD4+CD25+ cells markedly inhibited division of CD4+CD25 cells. However, both the CD4+CD25 and CD4+CD25+ populations divided when IL-2, IL-4, or anti-CD28 were added to the cocultures. Although the division of CD4+CD25 cells led to distinct peaks of CFSE dilution, the division of CD4+CD25+ cells consistently showed a more diffuse pattern of CFSE dilution.
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Although both CD4+CD25 and CD4+CD25+ cells proliferated in the presence of exogenous IL-2, IL-4, and anti-CD28, the possibility remained that the CD4+CD25+ cells remained functional with respect to their ability to inhibit IL-2 mRNA. When measured by quantitative PCR (qPCR), 3 maximum levels of IL-2 mRNA were observed under these limiting culture conditions after 44 h of stimulation (data not shown). Fig. 2 is divided into two parts with the results of the [3H]TdR uptake assay on the left side and the corresponding qPCR analysis of the same cell populations on the right. In agreement with our previous Northern analysis (14), the transcription of IL-2 mRNA in CD4+CD25 cells was inhibited in the presence of CD4+CD25+ cells (Fig. 2A). When IL-2 (Fig. 2A) or IL-4 (Fig. 2B) were added to the cultures, the levels of IL-2 mRNA were not significantly different in CD4+CD25 cells stimulated in the absence of CD4+CD25+ cells and were never induced in CD4+CD25+ cells alone. However, IL-2 mRNA (Fig. 2A) and IL-4 mRNA (data not shown) were still inhibited. Thus, the proliferative response detected by [3H]TdR uptake and CFSE dilution was solely driven by the exogenous cytokines as CD4+CD25+ cells were functional and suppressed IL-2 mRNA. In these experiments, CD4+CD25 cells were not purified after coculture with CD4+CD25+ cells and it was possible that the decrease in IL-2 mRNA was a result of dilution from the additional cells. However, CD4+CD25+ cells comprise 33% of the sample while IL-2 mRNA inhibition was always greater than 80%. Furthermore, in preliminary experiments not depicted, greater than 75% inhibition of IL-2 mRNA was observed when CD4+CD25+ cells comprised only 20% of the coculture.
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60% of CD4+CD25 cells alone as well (data not shown). Thus, the addition of anti-CD28 partially abrogates the suppressive effect of the CD4+CD25+ T cells on IL-2 mRNA transcription in the CD4+CD25 responders. CD4+CD25+ cells require IL-2 to inhibit IL-2 transcription in CD4+CD25 cells
As recent in vivo experiments have strongly suggested that IL-2 is required for the generation and function of CD4+CD25+ T cells (17), we examined IL-2 mRNA in our coculture system in the presence of anti-IL-2 to determine whether IL-2 was also required for the activation of suppressor function. Although the addition of anti-IL-2 completely blocked the proliferation of CD4+CD25 cells alone (Fig. 3A), the addition of anti-IL-2 did not block the transcription of IL-2 mRNA (Fig. 3B), allowing us to examine the effect of anti-IL-2 on CD4+CD25+ function. The addition of anti-IL-2 to the coculture restored IL-2 mRNA (Fig. 3B). Thus, a certain level of IL-2 production by CD4+CD25 cells appears to be required to induce CD4+CD25+-mediated inhibition of IL-2 mRNA production. As IL-4 in the presence of a TCR signal can stimulate proliferation of CD4+CD25+ cells and induce CD4+CD25+ suppressor function (15), we also examined whether IL-4 could substitute for IL-2 in the induction of CD4+CD25+-mediated suppression. In the presence of IL-4 alone, the results were similar to those shown in Fig. 2B (data not shown). However, when IL-4 was added to the cocultures in the presence of anti-IL-2, IL-2 mRNA was not restored, indicating that IL-4 can substitute for IL-2 in vitro in inducing CD4+CD25+ suppressor function.
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| Discussion |
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A clear role for IL-2 in the generation, maintenance, and expansion of CD4+CD25+ cells in vivo has been convincingly established (17). The only exception to this is the observation that CD4+CD25+ T cells from mice that express the IL-2R
chain only in the thymus, and cannot respond to IL-2 in the periphery, exist in normal numbers and are capable of suppressing the development of the autoimmune syndrome that normally develops in IL-2R
chain-deficient mice. However, it remains possible that the output of these cells from the thymus is abnormally high secondary to the transgenic expression of the IL-2R
chain and that they retain their capacity to suppress for a certain period of time after receiving the IL-2 signal in the thymus. Their failure to survive and suppress autoimmunity upon transfer to IL-2/ mice is consistent with this scenario.
We have demonstrated here, for the first time, that IL-2 is also required for the activation of suppressor function of CD4+CD25+ T cells in vitro and that IL-4 can substitute for IL-2 in this process. An alternative explanation for this result is that IL-2/IL-4 function only as critical survival factors for CD4+CD25+ T cells in vitro. We believe this explanation is unlikely as we have recently demonstrated (15) that activation of suppressor function during preculture of CD4+CD25+ cells before their coculture with CD4+CD25 cells also required the presence of IL-2, yet no difference in the recovery of cells at 1 or 2 days was observed in the presence or absence of IL-2. In the present study, IL-2 mRNA was measured at 40 h of culture, when the effects of IL-2 on cell recovery were minimal.
It might be regarded as paradoxical that the action of one or the other of the two major T cell growth factors is required for subsequent suppression of their own production. However, the initial activation of effector CD4+CD25 T cells with resultant production of IL-2/IL-4 may be needed for regulation of the function of CD4+CD25+ T cells for two distinct purposes. First, it may facilitate the nonspecific expansion of the CD4+CD25+ T cells in situ at the site of the response. Although CD4+CD25+ T cells are nonresponsive to IL-2/IL-4 alone, they express high levels of the glucocorticoid-induced TNFR (GITR) and engagement of the GITR by an agonistic mAb (19) or its ligand 3 in the presence of IL-2 or IL-4 results in their proliferation in vitro. Recently, it has been shown that the GITR-L is expressed at high levels on resting APC, particularly B lymphocytes (20, 21). Second, the requirement for initial activation of effector cells before induction of suppressor function imposes a time constraint on when suppression can become manifest. Indeed, it would be highly desirable in the immune response to infectious agents that a certain level of effector function be established before induction of suppressor function which subsequently would lead to a down-modulation of effector function and the prevention of an overexuberant immune response (22).
| Footnotes |
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2 Current address: Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada, H3A2B4. ![]()
3 Abbreviations used in this paper: qPCR, quantitative PCR; GITR, glucocorticoid-induced TNFR. ![]()
4 G. L. Stephens, R. S. McHugh, M. J. Whitters, D. A. Young, M. Collins, and E. M. Shevach. Engagement of GITR on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. Submitted for publication. ![]()
Received for publication February 9, 2004. Accepted for publication March 29, 2004.
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