By
From the Department of Immunology, IMM4, The Scripps Research Institute, La Jolla, California 92037
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Abstract |
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Information on the turnover and lifespan of murine /
cells was obtained by administering
the DNA precursor, bromodeoxyuridine (BrdU), in the drinking water and staining lymphoid
cells for BrdU incorporation. For TCR-
/
(V
2) transgenic mice, nearly all
/
thymocytes
became BrdU+ within 2 d and were released rapidly into the peripheral lymphoid tissues.
These recent thymic emigrants (RTEs) underwent phenotypic maturation in the periphery for
several days, but most of these cells died within 4 wk. In adult thymectomized (ATx) transgenic mice, only a small proportion of
/
cells survived as long-lived cells; most of these cells
had a slow turnover and retained a naive phenotype. As in transgenic mice, the majority of
RTEs generated in normal mice (C57BL/6) appeared to have a restricted lifespan as naive cells.
However, in marked contrast to TCR transgenic mice, most of the
/
cells surviving in ATx
normal mice had a rapid turnover and displayed an activated/memory phenotype, implying a
chronic response to environmental antigens. Hence, in normal mice many
/
RTEs did not
die but switched to memory cells.
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Introduction |
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Gamma/delta T cells comprise a minor subset of the T
cells present in LNs and spleen (1, 2). Although they
clearly belong to the T cell lineage, /
cells differ from
conventional
/
T cells in many respects. In particular,
/
T cells recognize antigen in a manner fundamentally
different from
/
T cells. Thus, most
/
T cells are not
MHC restricted, and antigen recognition does not require
the processing pathways involved in generating peptide-
MHC complexes (2). Furthermore,
/
T cells have been shown to directly recognize nonpeptidic antigens, including phosphorylated nucleotides and prenyl pyrophosphate
(3). Structurally, TCR-
/
s may be more closely related
to Ig molecules than to TCR-
/
s, as suggested by primary sequence analysis (7). This differential recognition of
antigen implies that
/
T cells may have a very different
role than
/
cells in immune responses. In fact, it has
been suggested that
/
cells may serve as a component of the innate immune system, as they have more functional
similarities to macrophages and NK cells than to conventional T cells (8). A role for
/
cells in immune defense
was suggested by their in vivo expansion in response to
certain bacterial, parasitic, and viral infections (9). In
addition, antibody depletion of
/
cells and experiments
with the TCR gene knockout mice indicated that
/
cells
were important in the early response against intracellular bacteria (17). Nevertheless, the precise function of
/
cells remains unclear.
Understanding of the mechanistic basis of T cell function
has been aided by the examination of lymphocyte lifespan.
Thus, the in vivo lifespan of /
T cells has been extensively studied and has yielded important information about
the kinetics of thymocyte development, as well as the turnover of naive and memory T cells in the periphery (20).
In contrast, no similar information is currently available regarding the lifespan of
/
T cells. Here, we have investigated the lifespan of
/
T cells in both TCR-
/
transgenic and normal mice by following bromodeoxyuridine
(BrdU)1 incorporation in vivo. The results suggest that
/
T cells have a much more rapid turnover than do
/
T
cells, both during development in the thymus and after export to the peripheral lymphoid tissues.
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Materials and Methods |
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Mice.
B6, DBA/2, andBrdU Treatment.
Mice were given BrdU (Sigma Chemical Co., St. Louis, MO) in their drinking water at a concentration of 0.8 mg/ml. BrdU was dissolved in sterile water and was changed daily.Adoptive Transfer.
VAntibodies and Cell Staining.
Single cell suspensions were made from pooled LNs, thymus, or spleen and were surface stained using the following antibodies: Anti-V ![]() |
Results |
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The turnover of /
cells was examined in both TCR-
/
transgenic and normal mice. TCR transgenic mice will
be considered first.
TCR-/
Transgenic Mice
The advantage of TCR-/
transgenic mice is that the
numbers of
/
cells in these mice is far higher than in normal mice. We used the G8 TCR-
/
transgenic line, in
which the majority of T cells (50-75%) in LNs and spleen
express a V
2-containing TCR that reacts against gene products encoded in the T22/T10 region of the MHC (2, 26,
28). The nonclassical (class Ib) MHC antigen recognized by
G8 cells is expressed in H-2b but not H-2d mice. Hence,
G8
/
cells are generated in H-2d mice but are deleted in
the thymus of H-2b mice.
To distinguish between mature extrathymic /
cells and recent thymic emigrants (RTEs), we
compared adult thymectomized (ATx) versus sham thymectomized (STx) H-2d G8 mice. In terms of surface
markers, the vast majority of
/
(V
2) cells in spleen and
LNs of both STx and ATx mice expressed the typical
HSAlo CD44lo CD62Lhi phenotype characteristic of naive
T cells (Fig. 1). Cells with a memory phenotype, i.e.,
CD62Llo cells, were rare in STx mice (10-15%) but were
more prominent in ATx mice (30-35%); however, for other
markers memory-phenotype CD44hi cells and CD45RBlo
cells were inconspicuous (<10%), even in ATx mice. Thus,
the memory
/
cells in ATx mice did not express the
"complete" activated/memory phenotype (CD62Llo CD44hi
CD45RBlo) typical of
/
T cells (29). An unexpected difference between STx and ATx G8 mice was that
CD45RBint
/
cells were uncommon in ATx mice (10-
15%) but a dominant population in STx mice (65-70%).
Another striking finding was that total numbers of
/
cells
in spleen and LNs were four- to fivefold lower in ATx
mice than in STx mice (Fig. 2 A). These two findings suggested that the bulk of
/
cells in STx mice represented
short-lived RTEs expressing a CD45RBint phenotype. To
assess this possibility, we compared the turnover of
/
cells in STx versus ATx G8 mice.
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T cell turnover was examined by
placing mice on BrdU water for various periods and then
staining lymphoid cells for surface markers versus BrdU incorporation. When total V2+ cells were examined, BrdU
labeling of cells in LNs (Fig. 2 B) and spleen (data not
shown) occurred quite slowly in ATx mice and reached
only 30% of cells by 21 d. In STx mice, by contrast, labeling was rapid; thus, 45% of cells were labeled by day 7 and 70% by day 21.
Examining the surface markers on the BrdU-labeled cells revealed distinct differences between STx and ATx mice (Fig. 3). In ATx mice, the minor subsets of CD44hi, CD45RBint, CD45RBlo, and HSAhi cells had a rapid turnover. By contrast, the major subsets of naive CD44lo, CD45RBhi, and HSAlo cells had a very slow turnover; for CD62L expression, turnover was slow for both CD62Lhi and CD62Llo cells. However, all subsets in STx mice had a more rapid turnover than in ATx mice.
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There were two striking findings in STx mice. First, BrdU labeling of HSAhi cells was very high (70%) as early as day 2; however, labeling of HSAlo cells was very low on day 2 but reached 40% by day 7. The simplest explanation for this finding is that the RTEs released from the thymus in STx mice were initially HSAhi but then switched very rapidly to HSAlo cells. Second, BrdU labeling of the major population of CD45RBint cells in STx mice was significantly slower than for HSAhi cells but reached high levels by day 7 (70%); labeling of CD45RBhi cells, by contrast, was almost undetectable on day 7 but then rose to 30% by day 21.
These data on STx mice suggest that upon exit from the thymus RTEs were initially CD45RBint and then gradually switched to CD45RBhi cells over a period of several days. However, this transition occurred much more slowly than did the switch of HSAhi cells to HSAlo cells, which would explain why STx mice contained far more CD45RBint cells than HSAhi cells (Fig. 1). It should be noted that BrdU labeling of CD45RBhi cells was appreciably slower in ATx mice (10% at day 21) than in STx mice (30% at day 21). This finding suggests that BrdU labeling of CD45RBhi cells in STx mice was largely a reflection of the labeling of precursor cells (CD45RBint cells) within the thymus rather than postthymic division in response to environmental antigens.
Phenotype of RTEs.Since BrdU labeling of naive phenotype cells on day 2 was conspicuous in STx mice but almost undetectable in ATx mice, it follows that the labeled cells found at day 2 in STx mice represented a relatively pure population of RTEs. As predicted from the above data, these 2 d-BrdU-labeled cells were nearly all CD45RBint rather than CD45RBhi, and most of the cells were HSAhi rather than HSAlo (Fig. 4). Typical of the naive status of RTEs, the cells were also CD44lo and CD62Lhi.
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The data on the kinetics of BrdU labeling of CD45RBint and CD45RBhi cells in STx mice (Fig.
3) suggested that division of /
RTEs in the extrathymic
environment was minimal. However, whether RTEs differentiated into long-lived cells or died rapidly was unclear. To examine this question, STx mice were given BrdU
continuously for 14 d and then transferred to normal drinking water for a further 28 d (Fig. 5). This pulse-chase approach showed that most RTEs had only a brief lifespan.
Thus, after the BrdU pulse, the percentage of total BrdU+
cells declined by ~70% during the 28-d chase period (Fig.
5 A). Since total numbers of V
2 cells were largely unchanged during this period, the disappearance of BrdU+
cells could not be attributed to dilution of label.
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With regard to surface markers, the disappearance of
~70% of BrdU+ /
cells during the 28-d chase period applied equally to HSAlo, CD44lo, int, and hi, and CD62Llo and hi
cells (Fig. 5, B-E, compare with Fig. 3). However, the loss
of BrdU+ cells was much greater for the CD45RBint and
HSAhi subsets (90-95%), consistent with rapid differentiation of these cells into CD45RBhi and HSAlo cells, respectively. For CD45RBint cells, it is notable that the disappearance of these cells was paralleled by a twofold increase in
the proportion of BrdU+ CD45RBhi cells (Fig. 5 B), thus
providing direct support for the view that CD45RBhi cells
arose from CD45RBint RTE precursors. Despite this finding, the data as a whole suggest that 70% of RTEs died
within 1 mo of export.
The observation that substantial numbers of BrdU-labeled cells appeared in the periphery of STx (but not ATx) mice within 2 d implied that the
transit time of /
cells through the thymus was very rapid.
To examine this question directly, STx TCR-
/
transgenic mice were placed on BrdU and V
2+ cells in the
thymus analyzed (Fig. 6). By day 2, 90% of total V
2+ cells
were BrdU+ (Fig. 6 A). This rapid labeling also applied to
cells having the phenotype of RTEs, i.e., to CD45RBint,
HSAhi, CD44lo, and CD62Lhi cells (Fig. 6, B-E). These
data indicated that V
2+ thymocytes had a very rapid turnover and appeared to exit the thymus very soon after division. Interestingly, continuous administration of BrdU for up
to 21 d failed to label 5-10% of total V
2+ cells in the thymus (Fig. 6 A). These cells were predominantly CD45RBhi,
HSAlo, CD44hi, and CD62Llo (Fig. 6, B-E). Two explanations could account for the presence of these cells. First, a
fraction of the
/
cells generated in the thymus was unable to emigrate to the periphery and remained in situ for
an indefinite period of time. Second, some mature
/
cells were able to recirculate from the periphery back to the
thymus. Among
/
T cells, reentry into the thymus is restricted to activated cells (30). Whether the same restriction
applies to
/
cells has not been studied, although it is of
interest that the long-lived thymic
/
cells in the above
experiment were CD44hi CD62Llo, a phenotype associated
with activation/memory amongst
/
T cells. Therefore,
it was important to examine the phenotypic changes that
occurred after activation of mature
/
cells.
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To directly determine the phenotype of activated /
T cells, purified transgenic V
2+
LN T cells were adoptively transferred from H-2d G8 mice
into heavily irradiated H-2b (B6) or
2m
mice, and the
recipients were given BrdU for 4 d (Fig. 7). Since the T22/
T10 antigen is dependent upon
2m for its expression (31),
one would not expect the V
2+ cells to be activated after
transfer to the
2m
recipients. In fact, BrdU labeling of
V
2+ cells after transfer into
2m
mice was very low. By
contrast, after exposure to T22/T10 antigen for 4 d in normal B6 mice, virtually all of the injected V
2+ cells became
BrdU+; moreover, 15-fold more V
2+ cells were recovered from B6 than from
2m
hosts, indicating a marked
expansion of the cells to T22/T10 antigen in B6 mice. In
terms of surface markers, most of the V
2 cells in B6 hosts
displayed the typical CD44hi phenotype of activated cells.
At the early time point examined, the V
2 cells also
showed partial downregulation of CD45RB and CD62L.
For obscure reasons, TCR expression on the activated V
2 cells in B6 hosts was appreciably lower than for the V
2
resting cells in
2m
hosts.
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The above data indicate that exposure to specific antigen
caused V2 cells to divide and switch to an activated phenotype. In terms of CD44 and CD62L expression, these cells
closely resembled the minor subset of activated/memory-phenotype cells found in the thymus of G8 TCR transgenic mice (see above).
/
Cells in Normal Mice
The finding that the vast majority of V2 cells in G8
TCR transgenic mice had a naive phenotype implied that
the reactivity of this monoclonal population for typical environmental antigens was minimal. Therefore, it was considered important to examine the turnover of
/
cells in
normal mice. Data on the phenotype and turnover of V
2
and total
/
cells in ATx and STx normal B6 mice are
discussed below; the cells studied were prepared from pooled LNs and spleen. Quite similar data were seen in
DBA/2 mice (data not shown).
As mentioned earlier, the vast majority of V2+ cells in G8 TCR transgenic
mice consisted of naive phenotype cells, both in ATx and
STx mice (Fig. 1). The situation in normal B6 mice was quite different (Fig. 8 A). In these mice a high proportion
of V
2 cells in spleen and LNs displayed a CD44hi (memory) phenotype; CD44hi cells comprised ~45% of V
2
cells in STx mice and 85% in ATx mice. These findings
contrasted sharply with the phenotype of
/
cells (Fig.
8 B). Thus, for CD4+ cells (which consist almost entirely
of
/
cells), only a small proportion of these cells (25%)
were CD44hi in ATx B6 mice; the majority of CD4+ cells
were CD44int, the typical phenotype of naive
/
cells.
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BrdU incorporation by V2 cells
in ATx mice was largely limited to memory phenotype
CD44hi cells (Fig. 8 C). Since these cells comprised the
bulk of V
2 cells (Fig. 8 A), the labeling of total V
2 cells
in ATx mice was high and reached 70% by day 21 (Fig. 8
D). This high rate of labeling in ATx mice also applied to
total
/
cells, i.e., to cells detected with a pan anti-
/
mAb (Fig. 8 E). For CD44 subsets, the rate of labeling of
V
2 cells and
/
(CD4+) cells was quite similar, i.e., high
for CD44hi (memory) cells and low for CD44lo/int (long-lived naive) cells (Fig. 8 F). For other markers, BrdU labeling of CD45RB subsets of V
2 cells in ATx B6 mice was
much the same as for G8 TCR transgenic mice, i.e., high
for CD45RBlo (memory) cells and low for CD45RBhi (naive) cells (data not shown). As in G8 mice, labeling of
CD62Lhi and CD62Llo subsets of V
2 cells was quite similar (data not shown).
In marked contrast to ATx mice,
the turnover of naive phenotype V2 cells in STx mice was
rapid. Thus, BrdU labeling of CD44lo cells in STx mice
reached 40% by day 7, compared with <5% for ATx mice
(Fig. 8 C). It should be emphasized that naive phenotype V
2 cells were a major population in STx mice. Thus,
~50% of V
2 cells in STx were CD44lo/int cells, compared
with only 15% in ATx mice (Fig. 8 A). The substantially higher frequency of naive phenotype V
2 cells in STx
mice compared to ATx mice also applied to total cell numbers. Thus, total numbers of CD44lo/int V
2 cells in spleen
plus LNs were about fourfold higher in STx than in ATx
mice (data not shown). Thus, the implication is that, as in
G8 TCR transgenic mice, most naive V
2 RTEs generated
in B6 mice had a restricted lifespan.
The phenotype of RTEs in STx
mice is shown in Fig. 9. When control ATx mice were
placed on BrdU water for 7 d, most of the BrdU+ cells detected at days 4 and 7 were CD44hi/CD45RBlo memory
cells. Labeling of these memory phenotype cells was also apparent, although to a lesser extent, in STx mice. However, like G8 mice, STx B6 mice also contained discrete
populations of BrdU+ naive CD44lo and CD45RBint cells
(Fig. 9). Confirming previous findings on the /
RTEs generated in the normal thymus (24), the labeled V
2 RTEs
found in STx B6 mice were predominantly BrdUdim rather
than BrdUbright. As discussed elsewhere, the lower incorporation of BrdU by thymocytes compared to peripheral T cells
presumably reflects enhanced cold target competition from
DNA released by dying thymocytes (24).
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Collectively, the above data indicate that, as in G8 TCR
transgenic mice, the /
cells found in the periphery of
normal B6 mice comprised three broad categories of cells
with different turnover rates. In STx B6 mice, ~50% of
/
cells in spleen and LNs were RTEs; these cells probably incorporated BrdU exclusively in the thymus and then differentiated into typical naive resting cells in the periphery. In
ATx mice, a small proportion of RTEs survived for prolonged periods as long-lived naive cells with a very slow
turnover. However, in marked contrast to G8 mice, the
bulk of
/
cells in ATx B6 mice were memory phenotype
cells with a rapid turnover. This finding suggests that, after
export from the thymus, most RTEs in B6 mice did not die
rapidly but instead differentiated into memory cells through
contact with environmental antigens. The prominent conversion of naive RTEs to memory cells in B6 mice presumably accounts for the curious observation that the turnover of total V
2 cells in STx and ATx B6 mice was almost
identical (Fig. 8 C, left panel). Thus, numerically, the rapid
turnover of memory cells in ATx mice happened to balance the rapid production of RTEs in STx mice. This was
a clear contrast to G8 mice, for which the paucity of memory cells in STx mice led to much higher labeling of total
V
2 cells in STx than in ATx mice (Fig. 2 B).
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Discussion |
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Like /
T cells, the
/
T cells found in LNs and
spleen arise in the thymus and are subject to negative selection (1, 2, 8, 26, 32). Whether
/
cells undergo positive
selection is less clear (31). In the case of the G8 TCR
transgenic line (33) used here, and the closely-related KN6
line (34), the production of mature
/
cells was reported
to be much lower in
2-m-negative (
2m0) mice than in
2m+ mice, implying
2m-dependent positive selection.
However, another group studying G8 mice found low but
significant numbers of mature
/
cells in
2m0 mice and
concluded that the
/
cells generated in
2m+ H-2d mice
do not undergo positive selection but instead are subject to
a covert form of negative selection (35). This possibility is
difficult to reconcile with the finding that the production of G8 and KN6
/
cells is substantially less in
2m0 than
2m+ H-2d mice and that the residual
/
cells in
2m0
mice have strong reactivity for H-2b but display no detectable reactivity for H-2d even in the presence of added IL-2
(35). Moreover, the data reported here show that the RTEs
in
2m+ H-2d mice have a typical naive phenotype and do
not display signs of activation.
This study shows that the kinetics of thymocyte development is much more rapid for /
than
/
T cells. Studies
on
/
thymocytes have shown that immature CD4+8+
cells have a lifespan of ~3.5 d, whereas the turnover of the most mature thymocyte populations is much slower; these
findings apply both to normal and TCR transgenic mice
(20, 21). In contrast, we show here that, at least for TCR
transgenic mice, the vast majority of
/
thymocytes including those having the phenotype of RTEs became
BrdU+ within 2 d, indicating a very rapid rate of turnover.
Hence, if
/
cells undergo positive selection (see above),
this process must occur very rapidly. On the other hand,
positive selection appears to be a time-limiting step in
/
T cell development. Positive selection of
/
thymocytes
occurs soon after the transition of CD4
8
cells to cortical
CD4+8+ cells and induces a subset of these cells to differentiate into CD4+8
and CD4
8+ cells and migrate to the
medulla (38). Although these steps in positive selection occur within several days, the subsequent export of mature
/
cells from the medulla into the extrathymic environment is slow and can take up to 1-2 wk (20). The reason for the prolonged residence of
/
thymocytes in the thymic medulla is unknown, although an obvious possibility is
that additional selection steps are required before the cells
are able to emigrate from the thymus. Whatever the explanation for the slow export of
/
cells, our data suggest
that the release of
/
cells from the thymus occurs very
rapidly. Thus, in G8 TCR transgenic mice, large numbers
of labeled naive
/
cells were apparent in peripheral lymphoid tissues of STx (but not ATx) mice after only 2 d on
BrdU water. Hence, in contrast to
/
cells,
/
cells appear to be only dependent on the thymic microenvironment for a relatively brief period during their development.
It is of interest that /
RTEs expressed a semimature
phenotype. Thus, while RTEs resembled mature, naive
/
T cells in expressing low levels of CD44 and high levels of
CD62L, their phenotype was immature with regard to HSA
and CD45RB expression, i.e., the cells were HSAhi and
CD45RBint. These findings are consistent with the report
that after intrathymic injection of FITC, most of the labeled
/
cells released from the thymus were CD44lo
HSAhi cells (39). In this study,
/
RTEs matured from
HSAhi, CD45RBlo/int cells to HSAlo, CD45RBhi cells
within 7 d after export from the thymus. It has been similarly reported that for CD4+ cells
/
RTEs are initially
CD45RBint rather than CD45RBhi (24, 40). However, in
contrast to
/
RTEs, only a small proportion of
/
RTEs express an immature HSAhi phenotype (40, 41).
Therefore, a likely possibility is that those cells transiting
most rapidly through the thymus, including some
/
and
most
/
RTEs, exit as phenotypically immature cells. On
this point, it is of interest that nearly all
/
RTEs in the rat emerge from the thymus as Thy-1+ CD45RC
cells
and subsequently mature to a Thy-1
CD45RChi phenotype over a time span of 7 d (42). An interesting question then is whether the immature phenotype of rat
/
RTEs
also reflects rapid thymocyte kinetics. No information is
currently available on this point.
In addition to rapid turnover in the thymus, most naive
/
T cells were short-lived in LNs and spleen in both
TCR-
/
transgenic mice and normal mice. In TCR transgenic mice, the rapid turnover occurred in the absence of
antigenic stimulation and, therefore, presumably reflected
the death of naive cells. Thus, a rapid rate of output of
V
2+ cells from the thymus was balanced by a rapid loss of
cells from the periphery. A high proportion of the cells appeared to die at a semimature CD45RBlo/int stage. The loss
of RTEs was not an artifact of the monoclonality of the
V
2+ population in TCR transgenic mice, since rapid turnover of these cells was also observed in normal B6 mice.
Although most RTEs were short-lived, a small proportion
of these cells survived to become long-lived naive cells.
Thus, the majority of
/
cells in ATx transgenic mice,
and a minority of cells in ATx B6 mice, displayed a typical
naive (CD44lo HSAlo CD45RBhi) phenotype and had a
very slow turnover rate. Why these particular cells were selected for survival is unclear.
In nontransgenic B6 and also DBA/2 mice, it is of interest that most peripheral /
cells acquired an activated/
memory phenotype after thymectomy. Since these cells
were rare in ATx TCR transgenic mice, the transition of
naive to memory phenotype cells in B6 mice presumably
reflected an antigen-specific response to various environmental antigens. Unlike
/
cells found in epithelial tissues, peripheral
/
T cells express diverse TCRs and, therefore,
are presumed to recognize a wide array of different antigens. However, the high frequency of memory phenotype
/
cells in normal mice suggests that the
/
T cell repertoire rapidly becomes biased towards recognition of frequently encountered antigens. As a consequence, with advancing age the
/
T cell pool differs markedly from the
/
population in having only a very small reservoir of naive cells. In this respect, in contrast to
/
cells, the majority of
/
(CD4+) cells in ATx mice display a naive phenotype (24).
Although the rapid turnover of memory phenotype /
cells in normal mice presumably reflected continuous or intermittent contact with antigen, some of the BrdU labeling
may have represented bystander proliferation driven by cytokines, as has been observed for memory phenotype
/
cells (43). This possibility is worth considering, since IL-12
has been shown to stimulate proliferation of human
/
cells
in vitro (44).
For /
cells, a significant proportion of memory phenotype CD44hi cells were found to exclude BrdU for >1
mo (24). Similarly, >20% of CD44hi
/
cells in STx or
ATx B6 mice remained BrdU
after several weeks on BrdU
water (our unpublished data). For
/
cells, these BrdU
cells probably represent long-lived noncycling memory cells
specific for environmental antigens. However, whether
/
cells carry memory is still unclear. Most functional studies
pointing to a role for
/
cells in immune protection have
focused on the primary response. Nevertheless, experiments
with TCR-
/
and -
/
knockout mice showed that
/
cells do have a minor role in protection against a secondary
challenge with Listeria monocytogenes (18). In addition, alloreactive
/
TCR transgenic mice (on a SCID background) were shown to clear antigen-expressing cells more
efficiently if the mice were primed with antigen 12 d before
(45). These latter studies suggest that
/
T cells may have
some ability to mount a memory response to antigen. However, the phenotype of the cells responsible is unknown.
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Footnotes |
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Address correspondence to Jonathan Sprent, Department of Immunology, IMM4, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: 619-784-8619; Fax: 619-784-8839; E-mail: jsprent{at}scripps.edu
Received for publication 4 September 1997 and in revised form 26 November 1997.
David F. Tough's present address is The Edward Jenner Institute for Vaccine Research, Compton, Newbury, Berkshire RG20 7NN, UK.We thank Dr. S. Hedrick for the G8 mice.
This work was supported by grants AI-21487, AI-32068, CA-38355, and CA-25803 from the United States Public Health Service. D.F. Tough is the recipient of a Centennial Fellowship from the Medical Research Council of Canada.
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