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Division of Rheumatology and Immunology, Department of Medicine, University of Southern California School of Medicine, Los Angeles, CA 90033
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although it is well established that anti-CD3 mAbs induce T cell-dependent B cell differentiation (12, 13), mitogenic combinations of anti-CD2 mAbs generally lack this activity when added to PBMC. We report that this difference is caused when anti-CD2 triggers a novel inhibitory circuit that we have recently described (14). In this circuit, TGF-ß generated by NK cells appears to serve as a critical costimulatory signal to induce T suppressor cells.
TGF-ß is a multifunctional family of cytokines important in tissue repair, inflammation, and immunoregulation (15). TGF-ß can inhibit T and B cell proliferation, NK cell cytotoxic activity, and the generation of T cell cytotoxicity (16). By contrast, TGF-ß has been reported to promote the growth of murine CD4+ cells and CD8+ cells (17, 18). Besides its effect on T suppressor effector generation (14), TGF-ß has costimulatory activity for human CD4+CD45RA+ cells (19). Although almost all cells have the capacity to produce TGF-ß on stimulation, the cytokine is secreted as a latent complex and must be converted to its active form for functional activity (20).
We considered whether the different properties of anti-CD3 and
anti-CD2 mAbs could be explained by effects of the latter on NK
cells. At least 50% of NK cells display CD2 molecules (21), and
anti-CD2 can stimulate these cells to produce IFN-
(22) and can
enhance killer cell function (23, 24). In this report, we show that
anti-CD2 stimulates the production of TGF-ß and that NK cells are
the only lymphocyte population that constitutively secretes large
amounts of this cytokine. We also report that the contribution of
CD4+ T cells to the generation of
CD8+-regulatory cells is the production of IL-2 and have
demonstrated that the presence of both IL-2 and TGF-ß at the time
CD8+ T cells are activated conditions them to markedly
down-regulate IgM and IgG production.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PBMC were prepared from heparinized venous blood of healthy adult volunteers by Ficoll-Hypaque (Pharmacia, Piscataway, NJ) density gradient centrifugation. Separation of PBMC into monocyte and lymphocyte fractions was performed by centrifugation on a continuous Percoll (Pharmacia, Piscataway, NJ) density gradient (25). Depletion of lymphocyte subpopulations was performed by staining with anti-CD4 (OKT4, American Type Culture Collection (ATCC), Rockville, MD), anti-CD8 (OKT8, ATCC), or anti-CD16 (3G8 kindly provided by Jay Unkeless, New York, NY). Reacting cells were then depleted using immunomagnetic beads (Dynal, Great Neck, NY).
To obtain NK cells, PBMC were added to a nylon wool column, and the eluted, nonadherent cells were immediately rosetted with 2-aminoethylisothiouronium bromide-treated SRBC (26). The nonrosetting fraction was then stained with anti-CD3 and anti-CD74 (anti-HLA-DR) Abs and depleted of reacting cells using immunomagnetic beads (Dynal). This resultant population usually contained >98% CD56+, <0.5% CD3+, and <0.5% CD20+ lymphocytes. In some experiments, the NK cells were isolated by cell sorting using a FACStar (Becton Dickinson, San Jose, CA). PBL were stained with anti-CD3 and anti-CD20, and the nonstaining cells were collected.
CD4+ and CD8+ cells were prepared from nylon-nonadherent lymphocytes by negative selection using immunomagnetic beads. For CD4+ cells, the nylon-nonadherent cells were stained with Abs to CD8, CD16, CD11b, and CD74. The same Abs were used to obtain CD8+ cells except that CD4 was substituted for CD8. Purity of CD4+ cells was usually 95%, and that for CD8+ cells was 85 to 90%.
To obtain B cells, nylon wool-adherent cells were immediately rosetted with SRBC to remove any T cells and treated with 5 mM L-leucine methyl ester for complete removal of monocytes and functional NK cells. The resulting population was >92% CD20+ and <0.5% CD3+.
Reagents
Antibodies used were anti-CD2 (OKT11, ATCC); GT2 (27) made available by A. Bernard, Nice, France; T112 and T113 (1), kindly provided by S. Schlossman, Boston, MA; anti-CD3 (454 (28), a gift from W. Stohl, University of Southern California, Los Angeles, CA); anti-CD4 (OKT4, ATCC); anti-CD8 (OKT8, ATCC; CD8, Dako, Carpenteria, CA); anti-CD11b (OKM1, ATCC); anti-CD16 (3G8 (29), kindly provided by J. Unkeless, New York, NY); anti-CD20 (Becton Dickinson, San Jose, CA); anti-CD74 (L243, ATCC); anti-CD56 (Becton Dickinson). Anti-TGF-ß (1D11.16), a murine IgG1, was kindly provided by J. Carlino (Celltrix Pharmaceuticals, Santa Clara, CA) and Bruce Pratt (Genzyme Corporation, Farmington, MA).
Cell cultures
Procedures for cell cultures have been described previously
(30). In brief, the various lymphoid populations were added to the
wells of a flat-bottom microtiter plate (Falcon, Lincoln Park, NJ)
usually at 1 x 105/well in medium. To measure Ig
production, cultures were conducted in RPMI 1640 medium (Irvine
Scientific, Santa Ana, CA) supplemented with 10% heat-inactivated FCS
(Gemini Bioproducts Inc., Calabasas, CA), 10 g/ml gentamicin (Irvine
Scientific), 2 mM L-glutamine (Flow Laboratories, McLean,
VA), and 10 mM HEPES (U.S. Biochemical Corporation, Cleveland, OH).
Since TGF-ß can bind to serum components such as
2-macroglobulin or IgG (31, 32), supernatants to be
assayed for TGF-ß content were generated in Aim V serum-free medium
(Life Technologies, Grand Island, NY). The variation between triplicate
cultures was usually <10%.
For anti-CD2 stimulation, hybridoma supernatants of OKT11 and GT2 were added at 1:40 and 1:20, respectively. These concentrations were optimal for the induction of proliferative activity. To stimulate with anti-CD3, an optimal concentration of 1 µg/ml was added to the cells.
Generation of suppressor activity
Purified CD8+ T cells were incubated overnight
with either PWM (Sigma Chemical Co., St. Louis, MO) at 0.1 µg/ml or
Con A (Sigma Chemical Co.) at 1 µg/ml in the wells of 24-well plates
(Corning, Corning, NY). Added to these wells were IL-2 (10 U/ml) and/or
TGF-ß (0.1ng/ml). The next day cells were washed extensively to
remove any residual cytokine or mitogen. With Con A, cells were washed
in the presence of -methyl mannoside (Sigma). The CD8+
cells were then added to the wells of a flat-bottom microtiter plate
containing CD4+ cells, B cells, and anti-CD2.
Supernatants were collected after 7 days and assayed for Ig content by
an ELISA.
TGF-ß assay
Mink lung epithelial cells
(MLEC)4 that had been
transfected with an expression construct containing a truncated
plasminogen activator inhibitor (PAI-1) promotor fused to the
luciferase reporter gene were kindly provided by D. Rifkin, New York,
NY. TGF-ß was detected using these MLEC based on the procedure
described by Abe et al. (33). MLEC at 2 x
104/well were incubated with supernatants for 18 to
24 h at 37°C. To assay for luciferase activity, MLEC were lysed
by a cell lysis reagent (Analytical Luminescence, Ann Arbor, MI). Cell
lysates were then reacted with assay buffer and luciferin solution
(both Analytical Luminescence) immediately before being measured in a
luminometer (Lumat, Berthold Analytical Instruments Inc., Nashua, NH).
An example of the sensitivity and specificity of this assay for human
TGF-ß is shown in Figure 1
. To measure
total TGF-ß activity, samples were heated at 80°C for 2 min before
testing. In all assays, several concentrations of TGF-ß were included
to generate a standard curve, and the variation between triplicate
samples was always <10%.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As reported by others, PBMC were induced to produce IgM and IgG on
stimulation with anti-CD3 (12, 13). With GT2 and OKT11, a mitogenic
combination of anti-CD2 mAbs, there was generally little or no Ab
production (Fig. 2) although both
mitogens induced comparable levels of proliferative activity (25,
893 ± 5, 625 and 20, 619 ± 3, 605 cpm, respectively). A
similar result was obtained with another mitogenic combination of
anti-CD2 Abs, T112 and T113 (data not
shown).
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, depletion
of monocytes had no effect on Ab production. Depletion of
CD8+ cells resulted in the production of both IgM and IgG
production in all experiments, and depletion of CD16+ cells had a
similar effect in three of the four experiments.
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, in the
presence of anti-TGF-ß substantial amounts of IgM and IgG were
induced by anti-CD2. Anti-TGF-ß, however, had no effect on the
lymphocyte-proliferative response to anti-CD2. As expected, the
addition of anti-CD3 stimulated IgG production in the two donors
shown in Table III. In contrast to the
effect on anti-CD2, the addition of anti-TGF-ß had no effect
on anti-CD3-induced IgG production.
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shows that anti-CD2, but not
anti-CD3, stimulates the production of active TGF-ß. Thus, the
difference between anti-CD2 and anti-CD3 to induce Ig
production is inversely related to their ability to stimulate active
TGF-ß production.
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To determine the lymphocyte source of TGF-ß, PBL were depleted
of various lymphocyte populations and assayed for both latent and
active TGF-ß production either constitutively or after stimulation
with anti-CD2 (Table IV).
Production of total TGF-ß, both constitutive and stimulated, was
markedly reduced by removal of CD16+ cells but not by
depletion of CD4+ or CD8+ cells. Similarly,
depletion of CD16+ cells significantly reduced the
production of active TGF-ß. While the depletion of CD4+
cells had no effect, depleting CD8+ cells had variable
effects ranging from none to a significant reduction. This variability
probably reflects variation in the numbers of
CD8+CD16+ cells depleted in these
experiments.
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). Unlike T cells or B cells, purified
NK cells secreted nanogram per milliliter amounts of latent TGF-ß and
significant amounts of active TGF-ß. This level of TGF-ß activity
by NK cells was somewhat greater than that of monocytes, the more
conventional hemopoietic source of TGF-ß (34).
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. By contrast, purified T cells produced
negligible amounts of TGF-ß after 48 h of culture. A similar
finding was observed in five other experiments.
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Having shown that TGF-ß contributes to the inability of
anti-CD2 to stimulate Ab production, we considered the possibility
that this cytokine has an important role in the generation of
CD8+ suppressor activity. To determine when TGF-ß
was needed, anti-TGF-ß was added at different times to PBL
stimulated with anti-CD2. Figure 5
shows that, as before, the addition of anti-TGF-ß at the start of
the culture resulted in robust IgG and IgM production. A delay in the
addition of this Ab for only 24 h reduced IgG production by 50%
and IgM production by 80%. If anti-TGF-ß was added at 48 h
or later, the response was essentially abolished.
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shows that neither IL-2
nor TGF-ß alone were sufficient for the generation of suppressor
activity. However, when CD8+ T cells were exposed to both
cytokines, there was an 80% suppression of Ig production in the four
experiments summarized.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our second observation was that NK cells are a major source of TGF-ß. NK cells, but not resting B cells, CD4+ cells, or CD8+ cells, constitutively secrete substantial amounts of latent TGF-ß, as well as detectable amounts of the active form of this cytokine. While monocytes are generally regarded as a significant source of TGF-ß, unstimulated NK cells can secrete comparable amounts. Previously, we documented up-regulation of TGF-ß mRNA in NK cells following interaction with CD8+ T cells in PWM-stimulated cultures, and subsequently these NK cells produced active TGF-ß (14). In the present experiments, we found that NK cells could be directly stimulated with anti-CD2 to secrete increased amounts of active TGF-ß. Since a significant percentage of NK cells express CD2 but not CD3, this would account for the differential effects of Abs to these molecules on TGF-ß production and Ig production.
As is the case with other cellular sources of TGF-ß (37), the
cytokine is released predominantly as a latent complex and is converted
to its active form extracellularly. Early studies indicated that
cell-cell interaction was required for conversion. For example, with
bovine cells, active TGF-ß was produced when aortic endothelial cells
and pericytes were in contact but not when separated (38, 39). More
recently, however, Nunes et al. (40)found that activated macrophages
could produce active TGF-ß. Similarly, we have found that stimulated
NK cells can also produce active TGF-ß without the need for other
interacting cell populations. Rifkin and colleagues (20) have
demonstrated that an important step in active TGF-ß production was
the conversion of plasminogen to plasmin by the action of plasminogen
activator. Unlike T cells, NK cells secrete the urokinase-type
plasminogen activator (41), and 
50% express receptors for this
activator (42). Therefore, NK cells have the potential to convert
TGF-ß by such a mechanism. Of note, NK cells stimulated by
anti-CD2 increased active but not total TGF-ß production,
indicating that increased conversion was stimulated. However, whether
this is by plasmin activity must be determined.
Active TGF-ß has a variety of immunoregulatory activities (43, 44). We have previously shown that CD8+ cells stimulated in the presence of TGF-ß generated suppressor activity for Ab production (14). However, TGF-ß alone was insufficient, and CD4+ cells were also required to generate activity. This finding was highly consistent with previous reports describing a role for CD4+ suppressor-inducer cells. In the present study, we were able to replace CD4+ inducer cells with IL-2. A role for this cytokine in the generation of suppressor activity has been described in other studies (45, 46, 47). Consistent with our findings, IL-2 alone was not sufficient to generate this activity.
Our next significant observation was the critical timing of TGF-ß in suppressor cell generation. The presence of active TGF-ß was needed early, within the first 24 h. This was evident from studies where anti-TGF-ß was added at various times after lymphocyte stimulation with anti-CD2. At least a half-maximal Ab response reappeared if the addition of anti-TGF-ß was delayed for 24 h. Furthermore, conditioning of CD8+ cells with IL-2 and TGF-ß during the first 24 h of culture was sufficient for them to become suppressor cells.
The mechanism of action of CD8+ suppressor cells has not been determined. However, it is known that TGF-ß can up-regulate itself by paracrine and autocrine effects (48). Moreover, Kehrl et al. (17) reported that T cell-derived TGF-ß was not detectable until after 72 h of culture. We also found that T cells had no endogenous TGF-ß activity and speculate that NK cell-derived TGF-ß can prime them to produce large amounts of this cytokine. TGF-ß producing regulatory T cell clones have been described by others (49).
Although the administration of either anti-CD2 or anti-CD3 in
vivo (9, 10, 11, 50, 51) has immunosuppressive effects, only the infusion
of anti-CD3 results in severe systemic toxic side effects (52, 53, 54).
This is because of massive polyclonal T cell activation with
up-regulation of many cytokines which include IL-2, IL-6, TNF-, and
IFN-. The reasons for these differences between anti-CD2 and
anti-CD3 are poorly understood. CD2 molecules on the T cell surface
are in close proximity to the CD3/TCR complex and signaling through the
CD2 pathway in T cells is dependent on intact CD3 
-chains. Synergism
between the CD2 and the CD3/TCR receptor pathways has been demonstrated
(1, 2, 55). However, perturbation of certain epitopes on the large
cytoplasmic domain of CD2 can have inhibitory effects. For example, the
binding of an LFA-3 fusion protein to the CD58 binding site on CD2
inhibits T cell activation to a variety of stimuli and results in
anergy (56). The absence of severe toxic side effects following the
administration of anti-CD2 could, therefore, be due to negative
signaling.
Alternatively, these differential effects of anti-CD2 and anti-CD3 in vivo might possibly have a less complex explanation. Since NK cells display CD2 molecules (21), the action of anti-CD2 on both T cells and NK cells could promote the conversion of latent TGF-ß and trigger the TGF-ß-dependent inhibitory circuit. The resulting immunosuppressive effects could, therefore, abort the cytokine release associated with anti-CD3 therapy. While anti-CD2 administration in vivo results in the prolongation of graft survival and the amelioration of experimental autoimmune encephalomyelitis, neither of these effects is dependent on anergy (10, 11). Consistent with this suggestion, we found that following the depletion of NK cells, the effects of anti-CD2 mAbs on T cell-dependent B cell differentiation were equivalent to that of anti-CD3. Thus, once anti-CD2 up-regulation of TGF-ß production was blocked, the effects of each of these mAbs were now indistinguishable.
In addition to facilitating the generation of CD8+ T suppressor cells, NK cells have also been reported to have a role in the induction of CTL activity (57). Similar to our observation on T suppressor cell induction, CD4+ T cells by themselves were unable to induce CD8+ T cells to develop potent cytotoxic activity against allogenic target cells. The addition of NK cells provided costimulatory signals for the development of CTL activity. A possible relationship between the costimulatory signals supplied by NK cells in facilitating each of these CD8+ T cell effector activities remains to be investigated. Of interest, it has been reported that TGF-ß can up-regulate CTL activity (58).
It is likely that NK cells are involved in suppressor cell generation in vivo. They are abundant adjacent to the mucosal membranes that line the intestines (59), the lungs (60), and female reproductive organs (61). In each of these organ systems, the response to Ag stimulation is predominantly negative with an associated up-regulation of TGF-ß (62, 63, 64). Related to this is the predominant IgA Ab response (65, 66) and generation of regulatory cells that mediate oral tolerance (67, 68). We propose that the exposure of CD8+ T cells (and perhaps other T cell subsets) to TGF-ß coincident with activation may trigger the up-regulation of endogenous TGF-ß and enable these cells to produce immunosuppressive amounts of this or other inhibitory cytokines. In these organ systems, therefore, the presence of NK cell-derived TGF-ß may explain the predominantly negative immune response that occurs following Ag challenge to T cells.
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Acknowledgments |
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Footnotes |
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2 Current address: Third Department of Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita 010, Japan.
3 Address correspondence and reprint requests to Dr. D.A. Horwitz, Department of Medicine, Division of Rheumatology and Immunology, University of Southern California School of Medicine, HMR 711, 2011 Zonal Avenue, Los Angeles, CA 90033.
4 Abbreviation used in this paper: MLEC, mink lung epithelial cells.
Received for publication September 4, 1997. Accepted for publication November 17, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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