By
From the * Division of Hematologic Products, Center for Biologics Evaluation and Research, Food and
Drug Administration, Bethesda, Maryland 20892; the Laboratory of Molecular Genetics and
Immunology, The Rockefeller University, New York 10021; the § Dermatology Branch, National
Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and the
Laboratory of
Mammalian Genes & Development, National Institute of Child Health and Human Development,
National Institutes of Health, Bethesda, Maryland 20892
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Abstract |
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The family includes
,
, and Fc
RI
(Fc
). Dimers of the
family proteins function as signal transducing subunits of the T cell antigen receptor (TCR), the pre-TCR, and a subset of
Fc receptors. In mice lacking
/
chains, T cell development is impaired, yet low numbers of
CD4+ and CD8+ T cells develop. This finding suggests either that pre-TCR and TCR complexes lacking a
family dimer can promote T cell maturation, or that in the absence of
/
,
Fc
serves as a subunit in TCR complexes. To elucidate the role of
family dimers in T cell development, we generated mice lacking expression of all of these proteins and compared their
phenotype to mice lacking only
/
or Fc
. The data reveal that surface complexes that are expressed in the absence of
family dimers are capable of transducing signals required for
/
-T
cell development. Strikingly, T cells generated in both
/
/
and
/
/
-Fc
/
mice exhibit a memory phenotype and elaborate interferon
. Finally, examination of different T cell
populations reveals that
/
and Fc
have distinct expression patterns that correlate with their thymus dependency. A possible function for the differential expression of
family proteins may
be to impart distinctive signaling properties to TCR complexes expressed on specific T cell
populations.
![]() |
Introduction |
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The T cell antigen receptor (TCR) is a multimeric
complex consisting of subunits that function primarily
either in antigen recognition (/
or
/
) or signal transduction (CD3-
, -
, and -
, and a
family dimer) (1). The
family members constitute a group of structually and
functionally related proteins that include
,
(an alternatively spliced form of
), and Fc
RI
(Fc
; references 1, 2).
Thymocytes from mice lacking expression of both and
chain (
/
/
) are reduced in number and express extremely low levels of surface TCR relative to
/
+/+ mice
(3). Nevertheless, T cell development is not completely arrested in
/
/
mice as they contain both CD4+CD8+,
or double positive (DP),1 and CD4+ CD8
and CD4
CD8+, or single positive (SP) thymocytes and peripheral
SP T cells (3). In contrast, expression of the CD3 (
/
/
)
complex is absolutely required for thymocyte development, as mice lacking expression of CD3-
subunits fail to
develop beyond the the most immature CD4
CD8
, or
double negative (DN), stage (6). The transition of DN thymocytes into DP thymocytes is regulated by the pre-TCR,
a signaling complex composed of
chain, pre-T
, and
CD3 subunits, and which is also thought to include a
family dimer (7). The fact that low numbers of DP thymocytes (10-30% of normal) are generated in
/
/
mice
indicates that, though important,
and
are not essential for pre-TCR function. Likewise, the presence of low
numbers of SP thymocytes and peripheral T cells in
/
/
mice (3) demonstrates that
/
chains are not absolutely
required for
/
-TCR expression or for promoting T cell
development. Because of the extremely low levels of surface expression in
/
/
mice, the subunit composition of
surface pre-TCR and TCR complexes has not been accurately determined. One possibility is that the pre-TCR and
TCR can be expressed in the absence of a
family dimer,
and function, albeit inefficiently, to promote thymocyte development. Another possibility is that in
/
/
mice
the pre-TCR and/or
/
-TCR complexes associate with
Fc
chain homodimers, since Fc
is reported to be expressed during early thymocyte development (8). In
mice lacking Fc
, thymocyte development is unaffected,
and therefore Fc
normally does not play a significant role
in the development of thymus-dependent T cells (11).
Nevertheless, Fc
, together with
chain, functions as a
component of the TCR complex expressed on restricted
populations of T cells ("thymus-independent" T cells), and
in both Fc
/
and
/
/
mice these T cells express relatively high levels of surface TCR (4, 5, 10). In addition,
overexpression of Fc
chain (or
chain) in thymocytes
restores TCR surface expression and
/
-T cell development in
/
/
mice (12). Therefore, all of the
family
proteins are capable of independently supporting
/
-TCR
surface expression and promoting the development of
/
-TCR+ thymocytes.
In this study, we have generated mice lacking all three family proteins (
/
/
-Fc
/
mice) and compared the T
cell populations present in these animals to those found in
mice lacking either
/
or Fc
alone. The results provide
direct evidence that pre-TCR and
/
-TCR complexes
lacking a
family dimer are capable of supporting T cell
development, positive selection, and T cell activation.
Moreover, they reveal that, in the absence of specific stimuli, Fc
is not normally expressed in thymus-dependent T
cell populations, whereas both
/
and Fc
are expressed
in thymus-independent T cells. A possible function for the
restricted expression of different
family proteins may be
to modify the TCR signaling response in distinct populations of T cells.
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Materials and Methods |
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Mice.
The generation ofAntibodies and Multicolor Flow Cytometry.
mAbs used for flow cytometric analysis were purchased from PharMingen (San Diego, CA) and included fluorochrome (FITC or PE) or biotin-conjugated anti-CD4 (RM4.5); anti-TCR-Cell Preparations and Stimulation.
Thymus, spleen, and lymph nodes were excised from mice and single cell suspensions were prepared. Intestinal intraepithelial lymphocytes (i-IELs) were prepared from the small intestine as previously described (13). Dendritic epithelial T cells (DETCs) were obtained from trunk skin and were prepared as previously described (15). For thymocyte activation, DP thymocytes were isolated as previously described (16) and incubated at 37°C on plates that had been previously coated with anti-TCR-Cytokine Assay
For cytokine assays, purified T cells (106) were either cultured with media alone, media containing PMA (10 ng/ml; Sigma Chemical Co., St. Louis, MO) and ionomycin (1 µM; Sigma Chemical Co.), or plate-bound anti-CD3 ![]() |
Results |
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Mice lacking expression
of all family proteins (
/
/
-Fc
/
) were generated as
described in Materials and Methods. Examination of thymocytes from
/
/
-Fc
/
mice by FCM revealed a
phenotype essentially identical to that of
/
/
(Fc
+/+)
mice (Fig. 1 A). In addition,
/
/
and
/
/
-Fc
/
mice contained similar total numbers of thymocytes (10-
30% of normal, data not shown), which consisted almost
entirely of DN and DP cells. DP thymocytes from
/
/
mice express extremely low but detectable levels of TCR
as assessed by staining with anti-CD3-
(3-5, 14, and Fig.
1 A) and anti-TCR-
mAbs (3, 14). A similarly low but
discernable level of TCR surface expression was observed
on DP thymocytes from
/
/
-Fc
/
mice by FCM
(Fig 1 A). Significantly, although CD4+CD8
and
CD4
CD8+ SP cells were not readily detectable in the
thymus, SP T cells were present in the lymph nodes (data
not shown) and spleen (Fig. 1 B) of
/
/
-Fc
/
mice
in numbers similar to those observed in
/
/
mice (data
not shown). Together, these findings demonstrate that the
low but detectable level of TCR expression on DP thymocytes from
/
/
mice, and the ability to generate
"mature" SP T cells are not dependent upon the expression
of endogenous Fc
chain.
|
Thymocyte development has been shown to be severely
compromised at the DN stage in /
/
mice (17). Whereas
the most mature subset of DN thymocytes (CD44
CD25
)
constitutes 10-20% of the DN population in normal adults
and in mice lacking only Fc
(Fig. 1 C), these cells are
nearly absent in
/
/
mice (reference 17 and Fig. 1 C).
Examination of DN thymocyte subsets from both
/
/
and
/
/
-Fc
/
mice revealed a block at the identical
(CD44
/loCD25+
CD44
CD25
) stage of maturation
(Fig. 1 C), indicating that neither Fc
nor
/
chain is required
for thymocyte development before the CD44
/loCD25+
stage. Since the generation and subsequent expansion of
CD44
CD25
DN thymocytes is thought to be controlled
by signaling through the pre-TCR complex (7, 18), the
paucity of CD44
CD25
DN thymocytes in
/
/
mice
implies a function for
(and/or
) as components of the pre-TCR. However, the fact that some DP thymocytes are
generated in both
/
/
and
/
/
-Fc
/
mice indicates that the pre-TCR is capable, albeit inefficiently, of
transducing signals that promote the development of DN
thymocytes to the DP stage in the absence of all
family
proteins. To further evaluate the ability of surface complexes expressed on DN thymocytes in
/
/
-Fc
/
mice
to transduce signals that promote the formation of DP thymocytes, we generated
/
/
-Fc
/
RAG-1
/
mice.
Thymocytes from mice deficient in RAG-1 or RAG-2 are
blocked in their development at the DN stage but can be
induced to differentiate to the DP stage upon stimulation
with anti-CD3 mAb (19). Injection of anti-CD3-
mAb
into both
/
/
-Fc
+/+ RAG-1
/
(Fig. 1 D and reference 20) and
/
/
-Fc
/
RAG-1
/
mice (Fig. 1 D)
resulted in increased thymic cellularity (5-20× control)
and the generation of large numbers of DP thymocytes. Together these data demonstrate that both early and late
stages of thymocyte development are not absolutely dependent on the expression of
family proteins.
Maturation of DP thymocytes into SP T cells is controlled by
TCR-mediated signals that are received during positive selection in the thymus (21). Although DP thymocytes from
/
/
mice express barely detectable levels of surface TCR,
these TCR complexes are nevertheless capable of transducing signals that result in the positive selection of low numbers of thymocytes (3). Cross-linking of surface TCR
complexes on DP thymocytes from
/
/
mice results in
the upregulation of CD69 and CD5 (reference 14 and Fig.
2), events which are associated with positive selection in
vivo (22). To determine if a similar TCR-mediated signaling response could be elicited in thymocytes from
/
/
-
Fc
/
mice, DP thymocytes were stimulated in vitro with
antibodies directed against either CD3-
or TCR-
. Significantly, in vitro cross-linking of the TCR complexes on DP
thymocytes from
/
/
-Fc
/
mice with anti-TCR-
(Fig. 3) or anti-CD3-
(data not shown) induced upregulation of both CD69 and CD5. Moreover, the extent of CD5
and CD69 upregulation was similar in thymocytes from
/
/
-Fc
/
and
/
/
mice after stimulation (Fig. 2).
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|
To determine if the TCR complexes expressed on SP T
cells from /
/
-Fc
/
mice were also capable of transducing activating signals, we examined lymph node T cells for
expression of cell surface molecules associated with activation and memory. Surprisingly, although T cells from
/
/
-
Fc
/
mice express extremely low levels of surface TCR,
a high percentage of these cells appeared to have an activated or memory phenotype (i.e., CD44hi, CD62Llo; Fig.
3). A high percentage of SP T cells from
/
/
were also
CD44hi, CD62Llo, whereas the majority of T cells from
both control (
/
+/+-Fc
+/+) and Fc
/
mice displayed
a naive phenotype (CD44lo, CD62Lhi; Fig. 3). Nevertheless,
T cells from both
/
/
-Fc
/
and
/
/
mice were
largely refractory to direct TCR stimulation in vitro as they
did not appreciably increase levels of CD69 or IL-2R
and
proliferated poorly in response to treatment with cross-linking anti-TCR antibodies or anti-TCR plus anti-CD28
(data not shown).
We next examined the ability of T cells from /
/
and
/
/
-Fc
/
mice to produce cytokines after stimulation for 18 h with either PMA and ionomycin or anti-
CD3-
mAb. Stimulation of purified T cells from
/
/
and
/
/
-Fc
/
mice (as well as from Fc
/
and
/
+/+-Fc
+/+ mice) resulted in production of IL-2 (Table
1), but in all samples IL-4 and IL-10 remained undetectable
(data not shown). However, although T cells from
/
+/+-
Fc
+/+ and Fc
/
mice produced only low levels of IFN-
after stimulation, T cells from both
/
/
and
/
/
-
Fc
/
mice produced large quantities of IFN-
after stimulation (Table 1). A similar cytokine profile was observed
when cytokine production was assessed by RT-PCR (Fig.
4). IFN-
mRNA was also detectable in freshly isolated ex
vivo (unstimulated) T cells from
/
/
-Fc
/
mice and
/
/
mice by RT-PCR (Fig. 4). Since purified populations of T cells were used for these experiments, it is unlikely that IFN-
was derived from contaminating cell
populations, such as NK cells. Together, these findings indicate that despite their low levels of surface TCR, a high
percentage of T cells from both
/
/
and
/
/
-Fc
/
mice appear to be endogenously activated and exhibit a
Th1 memory cell phenotype.
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|
Distinct populations of lymphocytes have been defined within the intestinal epithelium (i-IELs, references 23, 24). Athough some of these
cells (CD4+ and/or CD8-/
+) appear to be dependent
on the thymus for their generation, those expressing a homodimer of CD8-
(CD8-
/
) are thought to arise through a thymus-independent developmental pathway
(24). Similar to peripheral (lymph node and spleen) CD4+
and CD8-
/
+
/
-T cells, thymus-dependent i-IEL
populations are unaffected in Fc
/
mice (11) but are reduced in number and are TCRlo/
in both
/
/
mice (4,
5, 25) and
/
/
-Fc
/
mice (data not shown). These
results are consistent with the idea that thymus-dependent
i-IELs express
/
but not Fc
during their development.
On the other hand, thymus-independent i-IELs have been
shown to express both
and Fc
chains (8), and mice lacking either
/
or Fc
contain
/
-TCR+ CD8-
/
+ and
/
-TCR+ i-IELs that express only moderately reduced
levels of surface TCR when compared with similar populations of i-IELs from
/
+/+-Fc
+/+ mice (references 4, 5,
and Fig. 5). Significantly, in the absence of
,
, and Fc
chains, all population of i-IELs (thymus-dependent and -independent) are TCRlo/
(Fig. 5).
|
To examine the lineage of TCR i-IELs in
/
/
-
Fc
/
mice, cells were analyzed for the presence of intracellular TCR-
and TCR-
chains. Interestingly, intracellular staining for TCR-
chains revealed that TCR-
/
lineage T cells are virtually absent in
/
/
-Fc
/
mice
whereas TCR-
/
lineage T cells are readily detected in the same animals (Fig. 5, bottom). Notably, TCR-
/
+ cells
are also markedly reduced in number in
/
/
mice, but
not Fc
/
mice, despite the fact that i-iELs from these animals express comparable levels of surface TCR (references
4, 5 and Fig. 5, 4th and 5th columns). Together, these findings indicate that either (a) the generation and/or survival
of TCR-
/
+ T cells is particularly dependent on expression of
/
chain, or (b) that Fc
is poorly expressed in developing
/
lineage T cells. Finally, these results demonstrate that expression of a
family dimer is required for
efficient TCR surface expression on all T cell populations
including both thymus-dependent and thymus-independent TCR-
/
+ and TCR-
/
+ cells.
We next examined mice lacking
expression of /
, Fc
, or all
family proteins for the presence of DETCs that express
/
-TCR and are thymically-derived (26). We observed that though present, DETCs
from both
/
/
mice and
/
/
-Fc
/
mice express
extremely low or undetectable levels of surface TCR, whereas
DETCs from Fc
/
mice express high levels of
/
-TCR
(Fig. 6 A). These results were unexpected as it had been previously reported that
/
mice contain DETCs that express relatively high levels of
/
-TCR (27).
|
We also examined thymocytes from /
/
and
/
/
-
Fc
/
for the presence of NK1.1+ T cells that are also
thymically derived but not necessarily thymus-dependent
(30). Although both
/
/
and
/
/
-Fc
/
mice
contained thymocytes of the expected "activation-NK"
phenotype (i.e., NK1.1+, IL-2R
+, CD44+, MEL-14
)
TCR+ cells were detectable only in
/
/
mice and these
cells were exclusively
/
-TCRlo (Fig. 6 B). Significantly,
although an earlier study had reported the presence of large
numbers of NK1.1+
/
-TCR+ thymocytes in
/
mice
(31), we found that NK1.1+
/
-TCR+ T cells were virtually undetectable in both
/
/
and
/
/
-Fc
/
mice (Fig. 6 B) . The most likely explanation for the striking variance between our results and those of previous
studies is that the latter analyzed
/
mice in which
chain is expressed (28); thus
chain most likely contributed to the TCR surface expression observed on DETCs and NK1.1+ thymocytes from these mice.
![]() |
Discussion |
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The results of this study demonstrate that "partial" TCR
complexes that lack family proteins (
,
, and Fc
) can
promote the maturation of at least some thymocytes. Indeed, thymocytes from
/
/
-Fc
/
mice appear to undergo a relatively normal developmental program; originating from precursor DN thymocytes they develop to the DP stage, undergo positive selection, and emerge as SP T cells.
T cells generated in
/
/
-Fc
/
mice express a functionally active TCR such that stimulation of these complexes by direct engagement results in the production of
specific cytokines. Collectively, these observations indicate that pre-TCR and TCR complexes that contain CD3 subunits but not a
family dimer can transduce signals normally associated with fully assembled TCR complexes.
Although some thymocytes are capable of developing in
/
/
and
/
/
-Fc
/
mice, the partial arrest that occurs at two specific checkpoints is revealing as to the in
vivo function of the
family dimers. Early DN thymocytes
from
/
/
mice can give rise to DP thymocytes; however, DP thymocytes are reduced in number as are their
immediate precursors (CD4
CD8
CD44
CD25
thymocytes). Since Fc
is reported to be expressed in early
thymocytes (8), and because transgenic Fc
can restore
development of DN CD44
CD25
thymocytes in
/
/
mice (13), it was possible that endogenous Fc
enabled the development of some thymocytes in the absence of
/
by
functioning as a component of the pre-TCR. However,
the observation that
/
/
and
/
/
-Fc
/
mice
contain similar numbers of DP thymocytes and show partial arrest at the same stage of development demonstrates
that
family members are not absolutely required for pre-TCR function. Notwithstanding, the markedly reduced
number of both DN CD24
CD44
thymocytes and DP
thymocytes in both
/
/
and
/
/
-Fc
/
mice argues that in the presence of a
family dimer, the pre-TCR is much more efficient at promoting this transition. The
other partial developmental arrest observed in both
/
/
and
/
/
-Fc
/
occurs during the transition of cells
from the DP to SP stage of development. SP thymocytes
are nearly undectable in
/
/
and
/
/
-Fc
/
mice,
yet both mice contain significant numbers of peripheral SP
T cells that accumulate with age. Thus
family proteins are also not absolutely required for late stages of T cell development. Nevertheless,
chain is required for efficient
TCR surface expression and
immunoreceptor tyrosine-based activation motif (ITAM)-meditated signals have been
shown to play an important role in positive and negative
selection of the T cell repertoire (32).
T cell receptors expressed on mature T cells from /
/
mice exhibit high affinity for self-ligand, a finding not observed in TCRs derived from normal mice (33). According
to signal strength models of selection, it is likely that only
those T cells with relatively high affinity for self-ligands are
positively selected and survive in
/
/
and
/
/
-
Fc
/
mice. The absence of
-mediated signaling during
thymic selection and the consequent selection of T cells
with high affinity receptors for self has a critical impact on
the phenotype and responsiveness of the mature T cells that
are generated. Indeed, despite their low levels of surface
TCR, a high percentage of T cells from both
/
/
and
/
/
-Fc
/
mice appear to be endogenously activated
and exhibit a Th1 memory cell phenotype. The high-affinity TCRs expressed by these cells could contribute to this
phenotype, as high affinity interactions, with a long association rate, could promote differentiation of cells towards
Th1 type memory cells by enabling coreceptor molecules to be effectively recruited into the receptor complex. Indeed, recent studies have suggested that individual cytokine
responses may be regulated in a hierarchical manner that
depends on the particular signaling threshold and the recruitment of costimulatory molecules (34). Although these
findings (34) are based on data obtained by varying the
concentration of ligand, our results would suggest that both
ligand density and TCR affinity influence the biochemical
response made by a particular T cell. Since T cells from
/
/
and
/
/
-Fc
/
mice express extremely low levels of TCR, the affinity of TCR-ligand interactions, rather
than the absolute number of TCR complexes that are engaged, could be critical for dictating the type of cytokine
response generated by T cells in our model. Alternatively, the skewing toward a Th1-like response in these mice may
also be reflective of the genetic background (C57BL/6) or
the functional alteration of NK1.1+ T cell populations that
are known to produce IL-4 (28). Whatever the foundation
for the Th1 phenotype, the generation of Th1 type cytokines appears to have important physiologic consequences
as a similar cytokine profile is exhibited by intestinal lamina
propria T cells in both
/
/
and
/
/
-Fc
/
mice
and these mice develop inflammatory bowel disease at extremely high frequency (Ono, M., T. Kawabe, E.W.
Shores, P.E. Love, and J. Ravetch, manuscript in preparation).
This and previous (4, 5, 8, 29) studies have served to reveal distinct patterns of expression for /
and Fc
during T cell ontogeny that correlate with the thymus dependency
of T cell populations. Most, if not all, thymus-dependent T
cells belonging to both the
/
-TCR+ and
/
-TCR+
lineages, including peripheral CD4+
/
-TCR+ and
CD8-
/
+
/
-TCR+ T cells, peripheral
/
-TCR+ T
cells, and dendritic epidermal
/
-TCR+ T cells express
very low or undetectable levels of surface TCR in the absence of
/
. On the other hand, "thymus-independent" T
cells such as CD8-
/
+ i-IELs express only moderately reduced levels of surface TCR in the absence of either
/
or Fc
and thus normally express both proteins. Several recent studies have demonstrated that Fc
is also expressed in
other T cell populations, such as NK1.1+ thymocytes and
T cells (35, 36) and lymphokine-activated
/
-TCR+ T
cells (37). However, these cells are clearly distinguishable from CD8-
/
+ i-IELs as they express extremely low levels of surface TCR in the absence of
/
. Since a common
property of these T cells is their responsiveness to cytokines, these observations suggest that expression of Fc
can
be induced by lymphokines. However, this property is not
universally shared by all T cell populations, as peripheral
CD4+
/
-TCR+ and CD8-
/
+
/
-TCR+ T cells do
not induce synthesis of Fc
after cytokine stimulation (reference 8 and our unpublished data).
The restricted expression of /
and Fc
in different T
cell populations also suggests that these proteins may perform specific functions, perhaps by quantitatively or qualitatively influencing the TCR signaling response.
chain,
which contains 3 ITAM signaling motifs appears optimized
to facilitate the development of thymus-dependent, self-MHC-restricted T cells. Indeed, thymocyte positive selection is markedly impaired in transgenic mice in which Fc
chain, which contains only a single ITAM, is substituted
for the
chain (13). The ability of
chain to amplify signals
resulting from low avidity TCR-ligand interactions is
therefore particularly critical for thymocyte selection (32).
On the other hand, the reduced signaling potential of Fc
chain may be important for limiting the responsiveness of
i-IELs and lymphokine-activated T cells to antigen. Thus,
the restricted potential of different T cell populations to express and use specific members of the
family as components of the TCR could be a mechanism for regulating the
T cell response to antigen.
![]() |
Footnotes |
---|
Address correspondence to Elizabeth W. Shores, FDA/CBER, 1401 Rockville Pike, HFM-538, Rockville, MD 20852. Phone: 301-827-1968; Fax: 301-480-3256; E-mail: shoresew{at}helix.nih.gov
Received for publication 4 December 1997.
1 Abbreviations used in this paper: DETC, dendritic epidermal T cell; DN, double negative; DP, double positive; FcWe thank Amy Rosenberg, Ronald Schwartz, Dorothy Scott, and Melanie Vacchio for reading the manuscript and for helpful discussion.
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References |
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