By
From the * Department of Microbiology and Immunology, The Pennsylvania State University College
of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033; Laboratory of
Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health,
Bethesda, Maryland 20892; and § Immunex Research and Development Corporation, Seattle,
Washington 98101
The commitment, differentiation, and expansion of mainstream /
T cells during ontogeny
depend on the highly controlled interplay of signals relayed by cytokines through their receptors on progenitor cells. The role of cytokines in the development of natural killer (NK)1+ natural T cells is less clearly understood. In an approach to define the role of cytokines in the commitment, differentiation, and expansion of NK1+ T cells, their development was studied in
common cytokine receptor
chain (
c) and interleukin (IL)-7 receptor
(IL-7R
)-deficient mice. These mutations block mainstream
/
T cell ontogeny at an early prethymocyte stage.
Natural T cells do not develop in
c-deficient mice; they are absent in the thymus and peripheral lymphoid organs such as the liver and the spleen. In contrast, NK1+ T cells develop in
IL-7R
-deficient mice in the thymus, and they are present in the liver and in the spleen.
However, the absolute number of NK1+ T cells in the thymus of IL-7R
-deficient mice is reduced to ~10%, compared to natural T cell number in the wild-type thymus. Additional data
revealed that NK1+ T cell ontogeny is not impaired in IL-2- or IL-4-deficient mice, suggesting that neither IL-2, IL-4, nor IL-7 are required for their development. From these data, we
conclude that commitment and/or differentiation to the NK1+ natural T cell lineage requires
signal transduction through the
c, and once committed, their expansion requires signals relayed through the IL-7R
.
Natural T (NT) cells are a distinct lineage of lymphocytes whose function is thought to be immunoregulatory in nature because they secrete a wide variety of cytokines, most notably IL-4, upon activation. They express
both natural killer (NKR-P1) and T ( Here we report that: (a) commitment and/or differentiation to NT cell lineage requires signaling through the common cytokine receptor Mice.
B6.IL-20/0 and IL-7R Mononuclear Cell Preparation.
Mononuclear cells (MNC) from
thymus and spleen were prepared by standard techniques. Intrahepatic MNC were prepared from minced liver lobes pressed
through a wire mesh. The cells were suspended in 50 ml of
RPMI-1640 (GIBCO BRL, Gaithersburg, MD) supplemented with 5% FCS (Hyclone Labs., Logan, UT) and allowed to settle
for ~10 min on ice. Liver MNC were separated from the hepatocytes by density centifugation over lympholyte M (Cederlane
Labs. Ltd., Hornby, Canada). Cells at the interface were collected
and washed with RPMI supplemented with 5% FCS.
Flow Cytometry.
Thymocytes (1-2 × 107) of individual animals 6 wk or older were stained for three-color flow cytometric
analyses, as described previously (5), with anti-heat stable antigen
(HSA)-PE (M1/69), anti-CD8 The loss of
To determine the absolute number of NT cells in the
wild-type and the various mutant mice, thymocytes from
them were electronically gated in the HSAlowCD8low population. The actual number of HSAlowCD8low cells was calculated from the observed percentages of this population, and the initial yield of thymocytes harvested from individual animals. Corresponding to the small size of the thymus
(16), the number of HSAlowCD8low cells was dramatically
reduced to ~5% of the wild type in IL-7R NT cells are also present in peripheral lymphoid organs such as the liver, spleen, bone
marrow, and lymph nodes; they also form a subset of intraepithelial lymphocytes of the gut (23). It is at present not
clear whether NT cells develop in situ in these organs or
whether they home here after their genesis in the thymus
(22, 24, 25). To determine whether
The requirement for signal transduction through Human and mouse NK cells are predicted to develop
from bipotential T/NK progenitor cells that commit to either T or NK cell lineage depending on the microenvironment of the developing precursor. Recent evidence suggests that the commitment to the NK lineage is strongly
influenced by IL-15 (31). If NT and NK cells have a
common precursor, then our data are consistent with the
hypothesis that commitment to NKR-P1+ T cell lineage
might be influenced by signals mediated by IL-15.
Two possible mechanisms can explain the lack of NT
cell development in Although IL-7R/
and
/
TCR)
cell markers. In mice, they are present in the liver, bone
marrow, spleen, lymph node, and postnatal thymus (for review see reference 1). The development of CD4+8
or
CD4
8
NT cells depends on the expression of nonclassical antigen presenting molecules such as CD1d1 (2) and
possibly H-2TL (5). They express highly conserved
/
TCR; a large majority of them express V
14J
281 (85%)
paired with V
8.2 (up to 70%) (6, 7). A similar subset of T
cells also exists among the human peripheral blood
CD4
8
lymphocytes (8, 9). Hence, NT cells are predicted
to serve an evolutionarily conserved function. Although
this function of NT cells remains elusive, their selective absence in autoimmune prone mice, such as MRL-lpr/lpr,
B6-lpr/lpr, C3H-gld/gld, and BWF1 (10, 11) as well as nonobese diabetic (NOD; 12), suggests a role in the control of
the disease. Moreover, the ability to delay or prevent the
onset of disease either by the adoptive transfer of NKR-P1+ splenocytes (10) that includes both natural killer and
NT cells, or by the administration of recombinant IL-4
(13), underscore the importance of NT cells in the physiology of normal immune responses.
chain (
c) because
c0/0 mice do
not develop NKR-P1+ T cells in the thymus or in the peripheral lymphoid organs, (b) the expansion of the committed NT cells requires signals relayed through the IL-7R
chain because although IL-7R
0/0 mice develop NKR-P1+
cells, they are dramatically reduced in numbers compared to
the wild type, and (c), signal(s) transduced through
c is not
mediated by IL-2, IL-4, or IL-7 because neither IL-20/0,
IL-40/0, nor IL-7R
0/0 mutations affect NT cell development.
0/0 mice were purchased from
the Jackson Laboratory (Bar Harbor, ME); B6.IL-20/0 were provided by D. Serreze (The Jackson Laboratory). R. Morawetz (National Institute of Allergy and Infectious Diseases, Bethesda, MD) provided B6.IL40/0 (14) and D. Roopenian (The Jackson
Laboratory) provided B6.
2m0/0 and B6.IL-40/0 mice. B6.
c0/Y
and B6.IL-7R
0/0 mice were bred and genotyped at the National
Heart, Lung and Blood Institute (Bethesda, MD; 15) and Immunex (Seattle, WA; 16), respectively.
-PE (53-6.7), anti-CD44-FITC
(IM7), and anti-NKR-P1 (NK1.1)-biotin (PK136), anti-TCR-
-biotin (H57-597), or anti-V
8.1,8.2-biotin (MR5-2). Thymocytes were also stained with anti-Ly6C-FITC (AL-21). When
staining with anti-IL-2R
-PE (TM-
1), anti-HSA-FITC, and anti-CD8
-FITC were used to electronically gate in the HSAlow
CD8low population. The biotinylated antibody was stained with
streptavidin-RED670 (GIBCO BRL). HSAlowCD8low thymocytes
were electronically gated and either CD44+NKR-P1+, CD44+
TCR-
/
+, and CD44+V
8.1,8.2+, Ly6ChighNKR-P1+, IL-2R
+
NKR-P1+, or IL-2R
+TCR-
/
+ NT cells were analyzed by
flow cytometry using a FACScan® (Becton Dickinson, Mountain View, CA). Intrahepatic NT cells were stained with anti-
NKR-P1-PE and anti-TCR-
-biotin or with anti-TCR-
/
-PE and anti-NKR-P1-biotin. Splenocytes were stained with
anti-B220-FITC (RA3-6B2), anti-TCR-
/
-PE and anti-NKR-
P1-biotin after blocking with anti-Fc
III/II receptor antibody
(2.4G2) for at least 15 min. NKR-P1+TCR-
/
+ cells were analyzed directly (liver) or after electronic gating within B220null
MNC (spleen). All antibodies used in these experiments were
purchased from PharMingen (San Diego, CA). Thymic NT cell
number was calculated from the percentages of the double-positive CD44+ and NKR-P1+, TCR-
/
+ or V
8.1,8.2+
thymocytes within the HSAlowCD8low subset as described previously (5).
NT Cell Ontogeny in the Thymus of c, IL-7R
-, IL-2-
and IL-4-deficient Mice.
c expression as found in
X-linked severe combined immunodeficiency patients or
in mice results in impaired development of mainstream
/
T cells (15, 17). To determine whether
c deficiency affects NT cell ontogeny, we examined their development in
the thymus of
c0/Y mice backcrossed to C57BL/6 for 4-8
generations.
c0/Y mice, >6 wk old, do not develop
HSAlowCD8low CD44highNKR-P1+ thymocytes, whereas
they are detected in the
c+/Y wild-type littermates (Fig.
1). Thus, akin to mainstream T cells, signaling through
c
is important for NT cell ontogeny.
Fig. 1.
Common cytokine
receptor c-deficient mice do not
develop thymic NT
/
cells.
Dot plots displaying CD44+
NKR-P1+ and CD44+TCR-
/
+ T cells among HSAlow
CD8low thymocytes of B6.
c0/Y
(seventh generation backcross to
C57BL/6) and B6.IL-2R
c+/Y
littermates. HSAlowCD8low thymocyte population was electronically gated and CD44highNKR-P1+ T cells were analyzed with a
FACScan® flow cytometer.
[View Larger Version of this Image (42K GIF file)]
c serves as an essential component of the multimeric receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 (18). To determine which of the cytokines that use
c receptor affect NT
cell development, the thymi of >6-wk-old B6.IL-20/0,
B6.IL-40/0 and B6.IL-7R
0/0 mice were analyzed. Mainstream T lymphocyte development is impaired in B6.IL-7
R
0/0 mice, but proceeds normally in B6.IL-20/0 (19) and
B6.IL-40/0 (20) mice. All three mutant mice develop
CD44highNKR-P1+ T cells (Fig. 2 A). The repertoire of
/
-TCR is skewed towards V
8.1,8.2 usage in >40%
(the percentage of TCR-
/
+ thymocytes that are V
8.1,
8.2+) of these NT cells (Fig. 2 A). Further data revealed
that the NT cells that develop in B6.IL-40/0 and B6.IL-7
R
0/0 mice also express Ly6C (Fig. 2 B) and that all the
three mutant mice express IL-2R
(Fig. 2 C) similar to the
NK1+ T cells that develop in the wild-type C57BL/6
mice. These data suggest that neither IL-2, IL-4, IL-7, nor
thymic stromal-derived lymphopoietin (TSLP; IL-7R
is a
receptor component of IL-7 and TSLP; 16) are required
for NT cell ontogeny.
Fig. 2.
IL-2-, IL-4-, and IL-7R-deficient mice develop thymic NT
/
T cells. (A) Dot plots
of CD44highNKR-P1+, CD44highTCR-
/
med, and CD44highTCR-
8.1,8.2med T cells among
HSAlowCD8low thymocytes of B6.IL-20/0 (n = 5), B6.IL-40/0 (n = 6) and B6.IL-7R
0/0 mice (n = 6). (B) Dot plots of Ly6ChighNKR-P1+ T cells among HSAlowCD8low thymocytes. (C) Dot plots of
IL-2 R
+NKR-P1+ (B6.IL-40/0 and B6.IL-7R
0/0) and of IL-2R
+TCR-
/
+ (B6.IL-20/0 and
B6.IL-7R
0/0) T cells among HSAlowCD8low thymocytes. In B and C, the percentage of NT cells was
almost equal in B6.IL-40/0, about half in B6.IL-7R
0/0, or up to twofold greater in B6.IL-20/0 compared with those in the wild type. (D) Absolute numbers of HSAlowCD8low thymocytes calculated as
the thymocyte number times the fraction of this subset. (E) Thymic NT cells in wild-type, IL-20/0,
IL-40/0 and IL-7R
0/0 mice. NT cell number was calculated from the percentages of the double-positive CD44+ and NKR-P1+, TCR-
/
+ or V
8.1,8.2+ thymocytes within the electronically gated
HSAlowCD8low population in D as described previously (5).
[View Larger Versions of these Images (67 + 33 + 20K GIF file)]
0/0 mice (Fig. 2
D). The absolute number of CD44+NKR-P1+ T cells
within the HSAlowCD8low population is reduced to ~40%
of wild type in IL-7R
0/0 mice (Fig. 2 E, top). However,
IL-7R
0/0 thymus contains only up to 10% of NT cells
that express TCR-
/
and V
8.1,8.2 compared to those
of the wild type (Fig. 2 E, middle and bottom). The remaining CD44+NKR-P1+ thymocytes in the IL-7R
0/0 mice
are probably natural killer cells that also express these markers, but not the TCR-
/
(22). The reduced number of
NT cells in the IL-7R0/0 mice then corresponds to the
small size of its thymus (16). In contrast, the absolute number of NT cells in IL-20/0 mice is increased by 1.5-2-fold
compared to the number of NKR-P1+ T cells in wild-type
animals (Fig. 2 E). These data suggest that signals delivered
through the IL-7R
are not only important in maintaining
thymic cellularity, but are also essential for the expansion of
NT cells.
c, IL-7R
,
and IL-2-deficient Mice.
c, IL-7R
, and IL-2
deficiency affect NT cell development and/or homing to the liver and spleen, the presence of NKR-P1+TCR-
/
+
cells was analyzed in these mutant animals. We find that
c
null mice contain dramatically reduced levels of NT cells in
the liver and spleen (Fig. 3). IL-7R
0/0 mice contained reduced numbers of NT cells in the liver (~60% of wild
type; Fig. 3 A) and in the spleen (~25% of wild type; Fig. 3
B). In contrast, IL-2 null mutations had increased levels of
NKR-P1+ T cells in the liver, but remained about the
same in the spleen (Fig. 3). Thus, although
c is required
for the development and/or homing of this subset of T
cells to the liver and spleen, the signaling for this process
does not require IL-2. Additionally, it is unclear whether
IL-7R
null mutation affects the development and/or
homing of NT cells to the periphery, or whether it affects the expansion of this T cell subset in the liver and spleen as it does in the thymus.
Fig. 3.
NT/
cells do not develop in peripheral lymphoid organs of
c-deficient mice, but develop in IL-7R
0/0 and IL-20/0 animals. Dot plots
displaying NKR-P1+TCR-
/
+ cells among mononuclear cells isolated from the liver (A) and spleen (B) of wild-type and mutant mice. Liver NT
/
cells were stained with anti-NKR-P1-PE and anti-TCR-
-biotin (B6.
c0/Y and B6.IL-7R
0/0) or anti-TCR-
-PE and anti-NKR-P1-biotin (B6.IL-2+/0
and B6.IL-20/0). Splenic NT
/
cells were stained with anti-B220-FITC, anti-TCR-
-PE and anti-NKR-P1-biotin, and identified among B220null
splenocytes. In all cases, the biotinylated antibodies were detected by staining with streptavidin-RED670. The staining pattern of intrahepatic NT cells
was observed in over 20 different preparations (see also reference 4).
[View Larger Versions of these Images (52 + 56K GIF file)]
c for
NT cell development that does not involve IL-2 and IL-4
as well as, by extension, IL-7 and TSLP (evidenced by their
development in IL-7R
0/0 thymocytes) as the soluble mediator is noteworthy. Thus, the lack of NT cells in
c0/Y
mice might be a reflection on the requirement for IL-9, IL-15, and/or an as yet unidentified cytokine as the signal transducer for their development. NKR-P1+ cells do not develop in mice with dysregulated expression of IL-2R
(26)
or when the IL-2R
function is blocked with specific antibody (27). Whereas IL-9 uses only
c as part of its receptor complex (28, 29), IL-15 function depends on both the
IL-2R
and
c (30). This suggests that IL-15 or a hithertofore undefined cytokine that uses both IL-2R
and
c
specifies the soluble mediator function for NT cell ontogeny. If indeed an IL-2R
and
c-dependent cytokine(s)
serves this function, how it selectively turns on NT cell development in fetal day 9 livers (25), and later in post-natal
thymus (7), remains to be determined.
c0/Y mice. Signaling through the
c
may be critical for the commitment of the precursor cell to
the NT cell lineage. An alternative mechanism would be
that further differentiation of the already committed NT
cells cannot proceed in the absence of signals from the
c. Current evidence supports the latter mechanism. It was recently demonstrated that
c null mice develop V
14 and
V
8 positive, the conserved TCR expressed by NT cells
(6, 7), thymocytes within their CD4
8
subset (34). However, these thymocytes poorly respond to in vitro cross-linking of their TCR by secreting IL-4 (34), a characteristic of mature NT cells (35). This would suggest that commitment to NT cells has occurred in the thymus of
c null
mice, but the committed precursor has not completely differentiated into this lineage.
0/0 mice develop NT cells, their absolute numbers in the thymus are dramatically lower (~10%)
than those found in the wild-type mice. In vitro stimulation of unfractionated thymocytes with IL-7 results in the
selective expansion of CD4+8
and CD4
8
thymocytes
that express the V
8.2 TCR (36). In keeping with this and
consistent with our results is the finding that IL-7 cytokine-deficient mice develop NT cells, but in reduced numbers (37). In this respect, it is also noteworthy that type I diabetes-prone NOD mice do not secrete IL-4 in response to in
vivo cross-linking of TCR (12) suggesting that they do not
develop NT cells. Type I diabetes is a Th1 disease that can
be delayed or prevented by the administration of IL-4 to
prediabetic NOD mice (13). The lack of IL-4 response of
NOD mice to in vivo TCR cross-linking is reversible by
IL-7 stimulation in vitro (12). Thus, in conclusion, akin to
mainstream T cells, the commitment and/or differentiation to the NT cell lineage depends on signal transduction
through the
c, and once committed, their expansion requires signals relayed through the IL-7R
.
Address correspondence to Sebastian Joyce, Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033. Phone: 717-531-4163; FAX: 717-531-6522; E-mail: sjoyce{at}bcmic.hmc.psu.edu
Received for publication 22 January 1997 and in revised form 27 May 1997.
S. Joyce is the recipient of the American Cancer Society's Junior Faculty Research Award. This work is supported in part by grants to S. Joyce from the American Cancer Society (Institutional), the Juvenile Diabetes Foundation International and the National Institutes of Health (RO1 HL54977).We thank M. Hunsinger and N. Schaffer for technical help; D. Roopenian for generous supply of B6.2-m0/0 and B6.IL-40/0 mice; D. Serreze for generous supply of IL-20/0 and IL-2+/0 mice and R. Morawetz for
B6.IL-40/0 mice for the initial experiments.
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