By
§
§
§
From the * Amgen Institute, Ontario Cancer Institute, and § Departments of Medical Biophysics and
Immunology, University of Toronto, Toronto, Ontario, Canada M5G 2C1
The interleukin-2 receptor chain (IL-2R
) is expressed on a variety of hematopoietic cell
types, including natural killer (NK) cells and nonconventional T lymphocyte subsets such as intestinal intraepithelial lymphocytes (IEL). However, the importance of IL-2R
-mediated signaling in the growth and development of these cells has yet to be clearly established. We have
investigated IEL and NK cells in mice deficient for IL-2R
and describe here striking defects
in the development of these cells. IL-2R
/
mice exhibited an abnormal IEL cell population,
characterized by a dramatic reduction in T cell receptor
CD8
and T cell receptor
lymphocytes. This selective decrease indicates that IEL can be classified into those whose
development and/or differentiation is dependent on IL-2R
function and those for which
IL-2R
-mediated signaling is not essential. NK cell development was also found to be disrupted in IL-2R
-deficient mice, characterized by a reduction in NK1.1+CD3
cells in the
peripheral circulation and an absence of NK cytotoxic activity in vitro. The dependence of NK
cells and certain subclasses of IEL cells on IL-2R
expression points to an essential role for signaling through this receptor, presumably by IL-2 and/or IL-15, in the development of lymphocyte subsets of extrathymic origin.
The cytokine interleukin-2 (IL-2) and its receptor (IL2R) have long been known to play a role of prime
importance in the activation and proliferation of T lymphocytes (reviewed in reference 1). However, it is unclear
whether signaling via the IL-2R is required for the normal
development and differentiation of other lymphoid or myeloid cells. The IL-2R is expressed on T lymphocytes (1), B cells (2), NK cells (3), neutrophils (4), and monocytes (5). The high affinity IL-2R is composed of three subunits, the The importance of individual IL-2R chains in signal
transduction has been clarified recently by the engineered
deletion of the gene product for each of the three known
receptor subunits. Given the diverse nature of the cytokine
receptors that contain the The importance of IL-2 and IL-15 in NK cell activation
and proliferation has been well documented (1, 8, 14). Because both cytokines signal via receptors containing the Mice.
Mice deficient in IL-2R Preparation of IEL.
Whole small intestine was removed from
mice and the lumen flushed with MEM medium. The intestine
was incised to expose the epithelial layer, and pieces ~1 cm in
length were shaken in 35 ml of MEM at room temperature for 30 min to displace IEL. Cells were passed through gauze to remove
intestinal debris and centrifuged at 1,000 rpm (250 g) for 5 min.
Cells were resuspended in 8 ml of 44% Percoll (Sigma Chemical
Co., St. Louis, MO), overlayed onto 67.5% Percoll, and centrifuged at 2,100 rpm (600 g) for 20 min. The interface was recovered, washed, and resuspended in Induction of NK Activity In Vivo.
Mice were injected intraperitoneally with 0.1 µg of polyinosinic:polycytidilic acid (poly[I]:
poly[C], Pharmacia, Upsala, Sweden) in 0.2 ml of PBS on day 0 and day 1. Spleens were removed on day 2, and mononuclear
cells (MNC) were isolated by density gradient centrifugation using Lympholite M (Cedarlane, Hornby, Ontario).
Induction of NK Activity In Vitro.
Spleen MNC isolated by
density gradient centrifugation were incubated with 10 ng/ml murine recombinant IL-12 (Genzyme, Cambridge, MA) for 18 h in
CM. After two washes in CM, viable MNC were counted and
cytolytic activity was assessed.
NK Cytotoxic Assay.
MNC obtained after in vivo or in vitro
induction of NK activity were added to V-bottomed plates (Microwell; Nunc, Raskilde, Denmark) in complete medium. The NKsensitive Moloney leukemia virus-induced mouse lymphoma cell
line YAC-1 was grown in CM, labeled with Na251CrO4 (NEN,
Boston, MA) (35 µCi/106 cells), and added to wells containing
effector cells. Target cell lysis was determined after a 4-h incubation by measurement of 51Cr release using the following formula:
percentage specific lysis = (a mAbs.
mAbs used in this study were as follows: anti-mouse
CD3 Flow Cytometry.
IEL cells, peripheral blood (PB) leukocytes,
or spleen MNC from poly(I):poly(C)-treated or untreated mice
were resuspended in 0.1 ml of PBS containing 1% BSA and 0.1%
sodium azide, and incubated with 2 µl of anti-CD32/CD16 (Fc
block; PharMingen) for 10 min at room temperature. Cells were
subsequently incubated on ice with mAbs for 30 min and analyzed by flow cytometry (FACScalibur®; Becton Dickinson, San
Jose, CA) using CELLQuestTM software (Becton Dickinson). Viable lymphocytes were gated on the basis of forward and side
scatter characteristics. A total of 10,000 gated events was analyzed
for each sample.
Evaluation of Cell Numbers in PB and Spleen.
Total numbers of
leukocytes in EDTA-anticoagulated blood and density gradient
(Lympholite M) purified spleen MNC were assessed by staining
with Turk's stain.
IEL cells, a unique subset of lymphocytes located between the epithelial cells of the gut mucosa, have been postulated to play a key role in mucosal immunity (15). IEL
constitute the most abundant extrathymic T lymphocyte
pool and exist as a heterogeneous population (16). In the
mouse, approximately half of IEL cells resemble peripheral
T cells in that they are Thy-1+ and TCR IEL have been found to express the intermediate affinity
form of the IL-2R (IL-2R
Table 1.
Expression of TCR, Thy-1, CD8, and CD4 in IEL of IL-2R,
, and
chains, whereas the intermediate affinity
form contains only the
and
chains (6, 7). Components
of the IL-2R have been identified in other cytokine receptors: the IL-2R
chain (
c, or common
chain) is common to the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors,
whereas the IL-2R
chain is shared between the IL-2 and
IL-15 receptors (8).
and
chains, and the wide
range of cell types that express components of the IL-2R,
the disruption of multiple immunomodulatory roles might
be expected in mice deficient for any one of the three subunits. Mice deficient in IL-2R
exhibit polyclonal T and B cell expansion (9), which correlates with a defect in activation-induced cell death in T cells, and the development of
autoimmune disorders and inflammatory bowel disease.
Similarly, in IL-2R
-deficient mice, T cells are spontaneously activated, resulting in plasma cell accumulation and
high levels of autoantibodies (10). IL-2R
-deficient mice
also show a defect in mature T and B cell development, but in contrast with the lymphoproliferation seen in IL-2R
-
and IL-2R
-deficient mice, a 10-fold reduction in absolute lymphocyte numbers is observed (11). In addition, NK
cells are completely absent in IL-2R
-deficient mice, and
the number of intestinal intraepithelial cells (IEL)1 cells is
severely diminished (11). In humans, loss of the
c function
leads to X-linked severe combined immunodeficiency
(SCID) (12), a disease characterized by multiple defects in
T, NK, and B cell development, as might be expected from
the impairment of several cytokine receptors (13). Thus,
signaling via components of the IL-2R plays an essential
regulatory role in homeostasis and autoimmunity.
and
chains, and because IL-2R
-deficient mice exhibit
profound defects in IEL and NK cell development, it was
of interest to examine the role of IL-2R
in these lymphocyte populations. We report here that expression of IL-2R
is crucial for the normal development of both TCR
and
TCR
CD8
IEL and for NK cells. These results suggest that certain cell populations that undergo extrathymic development and differentiation have an important developmental requirement for either IL-15 and/or IL-2.
were generated as previously
described (10) and maintained under specific pathogen-free conditions in our animal facility. Littermate controls were used
within experiments. Because IL-2R
-deficient mice develop severe autoimmune disorders with age (10), all assays were performed on mice 3-5 wk of age.
MEM containing 10% FCS
and Hepes (CM [complete medium]). The total number of cells
isolated at this step was counted as the total IEL cell number.
b / c
b) × 100%, where a = test release, b = spontaneous release, and c = release in the presence of 1% SDS. Spontaneous release was always <10%.
(FITC-conjugated, clone 145-2C11), anti-mouse Thy-1.2
(biotin-conjugated, clone 53-2.1), anti-mouse CD4 (FITC-conjugated, clone RM4-5), anti-mouse CD8
(biotin-conjugated,
clone 53-6.7), anti-mouse CD8
(PE-conjugated, clone 53-5.8),
anti-mouse TCR
(PE-conjugated, clone H57-597), anti-mouse
TCR
(FITC-conjugated, clone GL3), anti-mouse NK1.1
(PE-conjugated, clone PK136), and anti-mouse Ly-49A (PEconjugated, clone A1). All mAbs were from PharMingen (San
Diego, CA).
+. While most
of these IEL are CD8
+, some CD4+ and a few doublepositive cells are also present. In contrast, the remaining IEL
population expresses the CD8
homodimer and may be
either Thy-1+ or Thy-1
, and TCR
+ or TCR
+. Although it is generally believed that TCR
IEL develop in situ within the intestine, some controversy exists regarding
the origin of the various IEL subsets expressing TCR
(17). The evidence does, however, point to an extrathymic
origin for TCR
IEL expressing CD8
(18). This heterogeneity within the IEL compartment has made the exact
determination of IEL function and development difficult, and
little is known concerning the requirements for the normal
differentiation of these lymphocyte populations.
) (19), and examination of
IL-2R
expression has shown that IEL with high and low
levels of IL-2R
can be identified (20). To address the role
of IL-2R
in IEL cell development, flow cytometric analyses of IEL obtained from IL-2R
/
and IL-2R
+/
mice
were performed. Despite an equivalent number of total IEL cells, a distinctly different population profile was observed in IL-2R
/
mice compared with that in their IL-2R+/
or wild-type littermates. As shown in both Fig. 1 and Table 1, IEL from normal mice comprise heterogeneous populations
of TCR
+ and TCR
+ cells. However, IEL from IL2R
-deficient mice showed a preponderance of TCR
+
cells and a dramatic reduction in TCR
+ cells. The normal
ratio of
:
cells in IEL (shown here in IL-2R
+/
mice) is ~2:1, but this ratio was dramatically increased to
9:1 in IL-2R
/
mice. The number of Thy-1
IEL cells
was also profoundly decreased in the absence of IL-2R
. In IL-2R
+/
mice used as controls, more than half of
both TCR
+ and TCR
+ IEL were negative for Thy-1.
However, Thy-1
cells represented <5% of both
+ and
+ IEL in IL-2R
-deficient mice. Immunohistological
analysis revealed cells that stained positively with antiTCR
mAb, but not with anti-TCR
mAb (data not
shown), confirming the reduced number of TCR
+ IEL
observed using FACS® analysis. Similar results have been
reported for other cytokine receptor mutants. In IL-7R
knockout mice,
T cells (including
IEL) failed to develop, whereas
T cells (including
IEL) were present
in slightly reduced numbers, and NK cells were normal (21, 22; H. Kiyono, personal communication). The determination of
expression in spleen or lymph node cells
has proven to be problematic in IL-2R
-deficient mice
because of the increased
T cell and granulocyte populations occurring in these mutants. Because
cells normally
constitute only a small proportion of overall spleen and
lymph node cells, at this time we cannot distinguish between a relative and real decrease in
cell numbers in the knockout mouse as a whole.
Fig. 1.
Flow cytometric analysis of Thy-1, TCR, and TCR
expression on IEL from heterozygous (IL-2R
+/
) and homozygous (IL2R
/
) IL-2R
-deficient mice. IEL isolated from IL-2R
+/
or IL2R
/
mice were stained with anti-Thy-1 mAb, and anti-TCR
or
anti-TCR
mAb, and viable cells were analyzed by flow cytometry.
Numbers represent the percentage of total cells found in each quadrant.
[View Larger Version of this Image (74K GIF file)]
-deficient Mice
CD3+
CD3
(n = 4)
TCR
+ (n = 4)
TCR
+ (n = 3)
TCR
+ (n = 3)
CD8
+
CD8
+
CD4+
Thy-1+
Thy-1
Thy-1+
Thy-1
IL-2R
+/
33.0 ± 5.0*
38.2 ± 8.9
4.5 ± 1.0
36.3 ± 7.8
24.0 ± 12.2
15.3 ± 4.0
23.3 ± 3.1
31.6 ± 13.7
IL-2R
/
2.8 ± 2.1
56.0 ± 2.8
28.3 ± 1.0
91.3 ± 1.5
3.0 ± 1.0
7.5 ± 3.5
1.7 ± 3.5
34.4 ± 10.2
*
Numbers are mean ± SEM percentage of CD3+ cells (CD3+) or CD3 lymphocytes (CD3
) found in each quadrant as determined by FACS®
analysis.
When TCR+ IEL were analyzed for the expression
of CD8
and CD8
, a significant reduction in CD8
+
(CD8
) cells was observed in IL-2R
/
IEL compared
with IL-2R
+/
IEL (Fig. 2). Thus, IEL in IL-2R
-deficient mice can be characterized as lacking TCR
+ and
TCR
+ CD8
cells. Similar total numbers of IEL were
recovered after density gradient centrifugation of intestinal
cells in both IL-2R
/
mice (0.8 ± 0.2 × 106, n = 4)
and IL-2R
+/
mice (1.1 ± 0.2 × 106, n = 5). Only
TCR
+ CD8
+ or CD4+ cells were not reduced in
IL-2R
/
mice (Table 1). In fact, as previously reported
(10), the ratio of CD4:CD8 cells was elevated in IL-2R
/
mice. These results clearly show that two subpopulations of
IEL exist: an IL-2R
-dependent population, characterized
by expression of TCR
CD8
and TCR
, and an IL2R
-independent population, characterized by TCR
CD8
expression. Two distinct populations of IEL cells
have been previously described (23), from which it was
proposed that those IEL undergoing thymus-dependent
development display the CD8
+ marker and those that develop independently of the thymus express the CD8
homodimer. It has been postulated that this thymus-independent population differentiates from CD3
precursors present
in the gut wall (24), and that expression of CD8
on
these cells is induced by the immediate gut microenvironment. The presence of similar numbers of CD3
cells in
the IEL populations isolated from both IL-2R
+/
and IL2R
/
mice suggests that the reduction in CD8
+ IEL
observed in IL-2R
-deficient animals is not the result of a
lack of CD3
precursors in the gut wall, but rather due to a
lack of differentiation of these cells into CD8
+ cells,
possibly caused by a defect in gut microenvironment-IEL interaction. Therefore, we hypothesize that the establishment of a gut microenvironment that is permissive for the
development of lymphocyte subsets of extrathymic origin
is dependent on IL-15 and/or IL-2 through signaling via
the IL-2R
chain.
The role of IL-2R in NK cell development and function was also investigated in this study. NK cells are lymphocytes capable of non-MHC-restricted cytotoxicity against
virally infected and tumor cells (25), and activated NK cells
are known to express both the high and intermediate affinity IL-2 receptors (26). Because both forms of the IL-2R
contain the
chain, which is expressed at a high level in
resting NK cells (3), and anti-IL-2R
mAb treatment leads
to long-term elimination of NK cells in vivo (27), it was
thought that the IL-2R
chain might play a role in NK
cell function and development.
NK cell-mediated cytotoxicity was evaluated using spleen
MNC as a source of NK cells and the prototypic NK target
cell line YAC-1. No cytotoxic activity was apparent in unstimulated spleen MNC of 3-5-wk-old wild-type or mutant mice (data not shown). To study in vivo induction of
NK activity, mice were treated with the type I interferon
inducer poly(I):poly(C). While substantial NK cell-mediated cytotoxic activity was induced in IL-2R+/
mice, no
cytotoxic activity was apparent in spleen NK cells derived from IL-2R
/
mice (Fig. 3 A). To examine the activation of NK activity in vitro, spleen MNC from IL-2R
+/
and IL-2R
/
mice were incubated overnight with IL-12.
IL-12 induced significant cytolytic activity in MNC of IL2R
+/
mice but was completely ineffective in inducing
detectable NK cytolytic activity in IL-2R
/
MNC (Fig.
3 B). Analysis of IFN-
production (by ELISA [Intertest
;
Genzyme, Cambridge, MA]) in culture supernatants of
spleen MNC incubated with IL-12 revealed a 270-fold increase in IFN-
production over unstimulated controls in
IL-2R
+/
cells, but only a 2-fold increase in IL-2R
/
cells (data not shown). These results strongly indicate an
absence of functional NK cells in IL-2R
-deficient mice.
To determine whether the defect in IL-2R/
NK cell
cytotoxic activity was due to a functional inactivation of
NK cells or to a block in NK cell development, NK cell
numbers were evaluated using flow cytometry (as judged
by the presence of NK1.1+/CD3
cells). Absolute numbers of PB leukocytes and spleen MNC in IL-2R
-deficient mice were reduced compared with heterozygous
controls (Table 2). Flow cytometric analysis of lymphocytes
from PB (Fig. 3 C; Table 2) and spleen MNC (Table 2) in
untreated mice revealed a fivefold decrease in NK1.1+/
CD3
cells in IL-2R
-deficient mice. Similar results were
obtained for PBL and spleen MNC obtained from poly(I):
poly(C)-treated animals (data not shown). IL-2R
/
mice
also displayed an absence of Ly-49A+ cells both in peripheral blood and spleen (data not shown), confirming the absence of NK cells in these mice.
|
The IL-2R-deficient mice used in this study were generated using A129/J mice, a strain that is known to be negative for the NK1.1 surface marker of NK cells (28). It is
very unlikely that the absence of detectable NK1.1 surface
marker on IL-2R
/
cells was due to the presence of
A129/J background in these mice, because they had been
backcrossed into a C57BL/6 background five times. In all
littermates examined during the course of these experiments,
IL-2R
+/
mice showed consistent numbers of NK1.1+
cells, whereas IL-2R
/
mice always displayed very low
levels of NK1.1 staining. Inadvertent deletion of the NK1.1
gene due to colocalization with the the IL-2R
gene can
also be dismissed, since the NK gene complex (in which
the NK1.1, Ly-49, LGL-1, and NKR-P1 genes are clustered) is located on distal mouse chromosome 6 (29),
whereas the IL-2R
gene is localized on mouse chromosome 15 (30).
Although the chain subunit is essential for IL-2-mediated signal transduction, a defect in IL-2R
expression does
not affect the development of classical T cells (10). Several
studies have indicated that in both mouse and human, progenitor cells capable of differentiation into either T lymphocytes or NK cells are present in the thymus (31).
Those progenitors remaining within the thymus differentiate
into T cells, while those developing extrathymically become NK cells (31), implying that the immediate microenvironment provides the required signals for a specific differentiation pathway. Within the murine fetal thymus, this
bipotential progenitor cell population largely expresses not
only IL-2R
(34, 35) but also IL-15R
messenger RNA
(34), suggesting that these cells can respond to both IL-2
and IL-15.
It has been demonstrated that IL-2-deficient mice have
reduced but inducible NK cell-mediated cytotoxicity (36),
suggesting the existence of other compensatory IL-2R
binding molecules that may play a role in NK cell development. IL-15 shares many of the properties of IL-2 in its potentiation of NK cell cytokine production and cytotoxic
activity (14), and the IL-2R chain is common to the IL-2
and IL-15 receptors (8). The decrease in NK cell number
apparent in both IL-2R
and
chain knockout mice, together with the demonstration that IL-2 is dispensable for
NK cell development (36), suggests that IL-15 may be the
more critical molecule for NK cell development. This is
supported by the observation that IL-2R
-expressing fetal
thymic bipotential T/NK progenitor cells cultured with
IL-15 differentiated into functional NK cells capable of lysing YAC-1 target cells (34). High doses of IL-2 also induced differentiation into functional NK cells but did not
result in the same level of proliferation (34). It has also recently been reported that IL-15 is a maturation factor for
NK cells in vitro, capable of rescuing the development of
functional NK cells from mice in which the bone marrow
microenvironment (essential for the development of fully
functional NK cells) has been disrupted (37).
Investigation of the effect of IL-15 on the differentiation
of bipotential T/NK progenitor cells in fetal thymic organ
culture has shown that low doses of IL-15, but not IL-2,
induce the expansion of TCR CD8
T cells from this
progenitor population (34). This effect is blocked by the
addition of anti-IL-2R
mAb. Similarly, treatment in utero
with anti-IL-2R
mAb blocks the development of V
3+
dendritic epidermal cells (38), which are the developmental progeny of V
3+ fetal thymocytes (39). That this maturation may depend on IL-15-mediated (rather than IL-2-
mediated) signaling through the IL-2R
chain is suggested
by the observation that V
3+ dendritic epidermal cells are
present in IL-2-deficient mice (40). These results, taken
together with the reduction in TCR
CD8
IEL observed in this study, point to the importance of IL-2R
in
the development of extrathymic TCR
lymphocytes,
possibly as a component of the IL-15R.
Given that fetal thymic T/NK progenitors require IL2R expression for differentiation into
and NK cells (34),
it is possible that the block in development of TCR
CD8
and TCR
IEL observed in IL-2R
-deficient
mice lies at an early stage of progenitor differentiation
within the thymus. However, the presence of these IEL
subsets in athymic mice (41) suggests that it is the gut microenvironment itself that determines the surface phenotype of the cell, and that in the absence of appropriate
IL-2R
-mediated signaling in this location, extrathymic IEL
cannot develop. Likewise, although NK precursors are found
in the thymus, NK cell differentiation does not require the
presence of a thymus, suggesting that any developmental
block seen in IL-2R
-deficient mice is probably associated
with a block in development or differentiation in the periphery, possibly within the bone marrow microenvironment.
A subset of IEL expressing surface markers characteristic of
NK cells and capable of natural killing and antibody-dependent cell-mediated cytotoxicity has recently been described
(42). Interestingly, this subset is limited exclusively to the
thymus-independent TCR
CD8
or TCR
population. Therefore, it is fascinating to note that two distinct
lineages of lymphocyte capable of natural killing, the thymus-independent IEL (which can now be classed as NK-T
IEL), and classical NK cells, are both critically dependent
on IL-2R
for their normal development.
In conclusion, our observation that TCR CD8
IEL, TCR
IEL, and NK cells fail to develop in IL-2R
-
deficient mice is supportive of a major role for IL-15 in the
development of these extrathymic lymphocyte subsets. The
chain of the IL-15 receptor has recently been identified
and cloned (43), manipulation of which may help to clarify
the situation. The generation of a mouse with a gene-targeted disruption of the IL-15 gene will no doubt elucidate
further the role of IL-15 in NK and IEL cell development.
Address correspondence to Dr. Tak W. Mak, Amgen Institute, 620 University Avenue, Toronto, Ontario, Canada M5G 2C1. H. Suzuki's present address is Department of Immunology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 464, Japan. H. Takimoto's present address is Department of Immunology, Medical Institute of Bioregulation, Kyushu University 69, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan.
Received for publication 12 September 1996
H. Suzuki was supported by a post doctoral fellowship from the Cancer Research Institute, and T.W. Mak by the Medical Research Council of Canada.We thank Drs. H.-W. Mittrücker, J. Penninger, and T. Ohteki for critically reviewing the manuscript and Dr. M.E. Saunders for scientific editing.
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