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*
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland; and
Institute of Experimental Pathology, University of Ancona, Faculty of Medicine, Ancona, Italy
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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3.2 in association with Vß5.2. Moreover, these
Vß5.2+V3.2+ cells were shown to recognize
the recently described H-2Db-restricted epitope (CCLCLTVFL)
encoded in the leader sequence of the M-MuLV gag
polyprotein. Collectively, our data demonstrate a highly restricted TCR
repertoire in the CD8+ T cell response to M-MuLV-associated
Ags in vivo, and suggest the potential utility of
flow-microfluorometric analysis of Vß and V expression in the
diagnosis and monitoring of viral infections. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß
is a
heterodimer that recognizes small peptides associated with MHC class I
or II molecules. The specificity of the TCR is determined mainly by
three hypervariable complementarity-determining regions
(CDR)3 of the - and
ß-chains that are encoded either by the V domains (CDR1, CDR2) or by
the D and J elements (CDR3) (1). Until recently, the structural basis
of TCR recognition of peptide:MHC complexes could only be inferred
indirectly by binding and mutagenesis studies. However, the successful
crystallization of two TCR:peptide:MHC complexes (2, 3) has provided
new insights into this trimolecular interaction. As predicted by
earlier studies (4), it appears that the highly variable CDR3 regions
of the - and ß-chains play a predominant role in peptide binding,
while the CDR1 and CDR2 regions of V and Vß domains are involved
(depending upon the crystal analyzed) in peptide and/or MHC contacts.
This latter result provides a structural basis for the observation that
the T cell repertoire elicited by a particular peptide:MHC complex is
dominated frequently by a limited number of Vß and/or V domains
(reviewed in 5 .
Although most examples of Vß (or V) bias in recognition of defined
peptide:MHC complexes are based on sequencing of TCR from
long-term established T cell clones, we (6) and others (7) have shown
recently that a strong Vß (and/or V) bias can in some cases
already be detected by flow microfluorometry during a primary immune
response in vivo. Indeed, by immunizing normal DBA/2 mice with
syngeneic (P815) tumor cells transfected with the human HLA-CW3 gene,
we were able to detect a dramatic expansion of
CD8+Vß10+ T cells recognizing the decapeptide
CW3 170–179 in association with H-2Kd (6). At the peak of
the HLA-CW3 response, CD8+ T cells expressing Vß10 were
frequent in blood and lymphoid tissue of DBA/2 mice and were mainly
restricted to a subset with an activated
(CD62L-CD44highCD45RBlow)
phenotype (6, 8).
It could be argued that murine CD8+ T cell responses to a human HLA peptide expressed ectopically in transfected mastocytoma cells might represent an unusual (or even unphysiologic) model system. Therefore, we decided to investigate other well-characterized systems in which CD8+ mouse T cells are known to respond to more physiologic Ags. Moloney murine leukemia virus (M-MuLV) is a retrovirus that readily infects newborn mice and leads to the development of T cell lymphomas. Most strains of adult mice, however, are able to establish long-lasting immunity to the virus and reject M-MuLV-infected cells. The response of adult C57BL/6 and BALB/c mice to M-MuLV has been particularly well studied (reviewed in 9 . In these strains, CD8+CTL responses restricted by H-2Db and H-2Kd, respectively, have been shown to be protective. Moreover, the dominant epitope recognized by H-2Db-restricted CTL in the response to the closely related Friend/Moloney/Rauscher (FMR) group of retroviruses has been identified very recently (10).
In the present study, we have determined the TCR repertoire of
CD8+ T cells in C57BL/6 or BALB/c mice responsive to M-MuLV
Ags in vitro and in vivo. Our data indicate that there is a dramatic
Vß and/or V restriction in both strains, thereby strengthening the
case for generalized oligoclonal CD8+ T cell responses to
Ags and pathogens.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 and BALB/c mice were obtained from HARLAN OLAC (Bicester, U.K.). M-MuLV-infected MBL-2 and LSTRA tumor cells were maintained by weekly passage in syngeneic C57BL/6 and BALB/c mice, respectively (11). For primary immunization, 50 x 106 irradiated (10,000 rad) tumor cells were injected i.p. into syngeneic mice. After 3 to 4 wk, secondary responses were elicited by i.p. injection of 10 x 106 viable syngeneic tumor cells. PBL and nylon wool-purified peritoneal exudate cells (PEC) were prepared as described previously (6).
Production of virus-immune and "carrier" mice
Cellfree preparations of Moloney murine sarcoma virus/M-MuLV complex obtained from progressing sarcomas induced in 2-wk-old C57BL/6 and BALB/c mice were used throughout this study. Adult (8–10 wk old) mice were injected i.m. in the thigh region with the syngeneic extract at a dose that had an Moloney murine sarcoma virus in vitro titer of 1 to 1.2 x 105 focus-forming U/ml on 3T3/FL cells, and M-MuLV titer of 0.8 to 1 x 106 plaque-forming U/ml on SC-1 XC cells. These mice developed tumors that regressed in all instances within 14 days and were used as M-MuLV-immune spleen cell donors.
To obtain virus carrier mice (12), C57BL/6 and BALB/c mice were injected s.c., within 48 h after birth, with 0.05 ml of 0.1 gEq cellfree extract of a primary leukemia induced by M-MuLV in BALB/c mice. When these mice were 10 to 12 wk old, they served as virus carrier spleen cell donors.
Mixed lymphocyte:tumor cell cultures and CTL clones
Virus-specific CTL were generated in vitro in a 5-day mixed leukocyte tumor cell culture (MLTC) (13). Briefly, 25 x 106 responder spleen cells from M-MuLV-immune mice and 5 x 106 irradiated leukemic (MBL-2 or LSTRA) or 2 x 107 stimulator spleen cells from carrier mice were cocultured in 15 ml of DMEM (Life Technologies, Paisley, U.K.) supplemented with 2 x 10-3 M L-glutamine, 2 x 10-2 M HEPES, 3 x 10-5 M 2-ME, antibiotics, and 10% heat-inactivated FCS (Irvine Scientific, Santa Ana, CA). Cells recovered from MLTC were washed and maintained for an additional 4 days in culture (2 x 106 cells/ml) in complete medium supplemented with 10 U/ml of rIL-2 (a generous gift of Sandoz, Basel, Switzerland) to permit the cytofluorometric analysis of TCR Vß expression. CTL clones were established by plating MLTC cells at limiting dilution, as described previously (14).
Cytotoxic assays
CTL clones or nylon wool-purified PEC from M-MuLV-immune mice were used as effector cells. Target cells were either MBL-2 lymphoma (M-MuLV infected, H-2b), RMA lymphoma (Rauscher virus infected, H-2b), or EL-4 lymphoma (FMR uninfected, H-2b). The FMR gag-encoded epitope CCLCLTVFL (10) was synthesized and purified by standard procedures and dissolved in DMSO. For cytotoxic assays, effector cells and 51Cr-labeled target cells were mixed at the indicated ratios in the presence or absence of various concentrations of peptide. Supernatants were harvested after 4 h, and specific 51Cr release was calculated as described previously (11).
Flow microfluorometry
At various times after primary or secondary immunization with
syngeneic M-MuLV-infected tumor cells, C57BL/6 or BALB/c mice were bled
by the tail vein and PBL isolated by Ficoll-Hypaque gradient
centrifugation. Isolated PBL were routinely triple stained with mAbs to
CD8 (53-6.7), CD62L (Mel-14), and a panel of anti-Vß mAbs
including Vß2 (B20.6), Vß3 (KJ25), Vß4 (KT4), Vß5 (MR9–4),
Vß5.1 (MR9-8), Vß6 (44-22), Vß7 (TR310), Vß8 (F23.1), Vß9
(MR10-2), Vß10 (B21.5), Vß11 (RR3-15), Vß12 (MR11-1), and Vß14
(14-2). In some experiments, four-color analysis of PBL from
M-MuLV-immune C56BL/6 mice was performed using mAbs to CD8, CD62L, and
Vß5 in conjunction with a panel of anti-V mAbs including V2
(B20.1), V3.2 (RR3-16), V8 (B21.14), and V11 (RR8-1). CTL
clones or MLTC cells were normally double stained with mAbs to CD8 and
Vß or V. All samples were gated on viable cells (assessed by light
scatter) and run on either a FACScan or FACStar (Becton Dickinson, San
Jose, CA) equipped with LYSIS II software.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD8+CTL clones specific for M-MuLV-associated Ags
can be generated readily in MLTC established from virus-immune BALB/c
or C57BL/6 mice (11). Using a panel of anti-Vß mAbs, we screened
the Vß repertoire of established M-MuLV-specific clones from these
two strains. As shown in Table I
, the
Vß usage of such clones was remarkably restricted in both cases. In
particular, 38 of 41 BALB/c clones utilized Vß4, and 35 of 35 C57BL/6
clones used Vß5. This Vß preference was already clearly established
among CD8+ T cells in MLTC from which the clones were
derived (Table II). Thus,
CD8+Vß4+ and
CD8+Vß5+ cells were enriched by three- to
fivefold in MLTC established from BALB/c and C57BL/6 mice, respectively
(as compared with normal or immune spleen cells). Comparable results
were obtained in mixed cultures using either irradiated virus-infected
(carrier) spleen cells or tumor cells as stimulator cells (Table II),
indicating that the selective Vß expansion was specific for
M-MuLV-associated (rather than tumor-specific) Ags. No significant
Vß-specific expansion of CD4+ T cells was observed in
MLTC under the same conditions (Table II).
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To investigate whether the observed in vitro Vß bias in the
CD8+ T cell repertoire to M-MuLV-associated Ags also
occurs in vivo, C57BL/6 or BALB/c mice were injected with irradiated
syngeneic M-MuLV-infected (MBL-2 or LSTRA) tumor cells and boosted with
viable syngeneic tumor cells 2 to 4 wk later. This protocol has been
shown previously to be optimal for the generation of M-MuLV-specific
CTL (11, 14). PBL were pooled from immunized or control mice on day 10
and stained with a panel of anti-Vß mAbs together with mAbs
against CD8. To increase the sensitivity of detection of responding
CD8+ cells, mAbs against CD62L (Mel-14) were included in
the third color (8). As shown in Figure 1, PBL from C57BL/6 mice were highly
enriched for Vß5+ cells in the activated
(CD62L-) subset of CD8+ cells following
secondary immunization with syngeneic MBL-2 tumor cells. In contrast,
all other Vß tested were utilized less frequently among
CD62L-CD8+PBL. In PBL of BALB/c mice similarly
immunized with M-MuLV-infected syngeneic LSTRA tumor cells,
Vß4+ cells were selectively enriched in the
CD62L-CD8+ subset (Fig. 1). No Vß bias was
seen among CD62L-CD4+PBL in both strains (data
not shown).
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, CD8+CD62L-PBL
from M-MuLV-immunized C57BL/6 mice were highly enriched in cells that
reacted with a pan anti-Vß5 mAb, but were depleted of
Vß5.1+ cells. In contrast,
CD8+CD62L+PBL from immunized mice contained the
same proportion of cells reacting with both anti-Vß5 mAbs as the
equivalent population from unimmunized mice (Fig. 2). These data
indicate that the CD8+ T cell response to M-MuLV in C57BL/6
mice is highly restricted to Vß5.2+ cells. In accordance
with these in vivo data, flow-microfluorometric analysis of the 35
Vß5+CTL clones described in Table I
confirmed that 34
used Vß5.2 (data not shown).
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We also investigated the kinetics of appearance and persistence of
Vß5+CD62L- T cells in the peripheral
blood of C57BL/6 mice following secondary immunization with syngeneic
M-MuLV-infected MBL-2 tumor cells. As shown in Figure 3, the proportion of Vß5+
cells was maximally elevated in the CD62L- subset of
CD8+PBL as early as 6 days after secondary immunization and
persisted above background levels for at least 70 days. In contrast, no
change in the proportion of Vß5+ cells was observed at
any time in the CD62L+CD8+PBL subset. Although
some variation in the proportion of
Vß5+CD62L-CD8+PBL was seen
between individual immunized mice, the overall evolution of the
response was quite consistent (Fig. 3).
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We have shown recently that the CD62L- subset of
CD8+Vß10+ T cells in DBA/2 mice reactive with
the H-2Kd-restricted epitope HLA-CW3 (170–179) expresses
lower levels of CD8 and TCR when compared with their naive
(CD62L+) counterparts (8). As shown in Figure 4, TCR and CD8 down-regulation is also
apparent in the CD62L- subset of
CD8+Vß5+ T cells responding to
M-MuLV-associated Ags in C57BL/6 mice. Quantitatively, the degree of
reduction in TCR and CD8 expression (2–3 fold) is very similar in both
antigenic systems, suggesting that down-regulation of both TCR and
coreceptor is a common feature of Ag-specific activation of
CD8+ cells in vivo.
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usage by CD8+Vß5+M-MuLV-immune T cells
Since T cell clones specific for peptide:MHC complexes frequently
exhibit restricted V (as well as Vß) usage, we also examined
M-MuLV-immune PBL populations from C57BL/6 mice with the currently
available mAbs against mouse V domains. To maximize the sensitivity
of this analysis, four-color staining was performed using mAbs against
CD8, CD62L, and Vß5 together with anti-V2, V3.2, V8, or
V11 mAbs. As shown in Figure 5,
CD8+CD62L-Vß5+PBL from
M-MuLV-immune mice were highly enriched in cells expressing V3.2
(
70%), whereas the other three V domains tested were
under-represented. In contrast,
CD8+CD62L+Vß5+PBL from immune or
normal mice contained only a small subset (5%) of cells that
coexpressed V3.2, as expected from previous studies (16, 17).
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A major advantage of flow-microfluorometric monitoring of immune
responses in vivo is that the absolute magnitude of the response can be
readily determined (6, 7). Representative data for 15 individual
M-MuLV-immune C57BL/6 mice measured at day 6 of the secondary response,
as well as five unimmunized control mice, are summarized in Figure 6. On average,
Vß5+CD62L- cells accounted for 20% of
the CD8 subset and 6% of total PBL in the immune mice. Interestingly,
absolute numbers of V3.2+ cells were increased similarly
in the CD62L-CD8+ subset (Fig. 6). Most
importantly, quantitation of CD8+CD62L- cells
that coexpress Vß5 and V3.2 resulted in absolute numbers that were
almost as high as for Vß5 and V3.2 alone (i.e., 11% of total
CD8+ cells and 3.3% of total PBL). Similar calculations
for Vß5+ and/or V3.2+ cells in the
CD62L+CD8+ subset failed to demonstrate any
difference between naive and immunized mice (data not shown).
Collectively, these data demonstrate that a remarkably high proportion
of specific CD8+ T cells can be found circulating in blood
at the peak of the M-MuLV response. Moreover, they indicate that
coexpression of Vß5 and V3.2 by these immune cells results in a
significantly enhanced sensitivity of detection when compared with
either the Vß or V domain alone (see
Discussion).
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3.2+M-MuLV-immune
T cells and clones predominantly recognize a dominantgag-encoded epitope
When this study was initiated, no information was available
concerning the epitope(s) recognized by the major
H-2Db-restricted CTL population responsible for
rejection of M-MuLV-induced tumors. However, Chen et al. (10) have
shown recently that most CTL specific for Ags encoded by the highly
related FMR family of retroviruses recognize a
H-2Db-restricted nonapeptide (CCLCLTVFL) encoded in the
leader sequence of the gag polyprotein. Since
Vß5+V3.2+ cells dominate the CD8 T cell
response to M-MuLV, we therefore tested several
Vß5.2+V3.2+CTL clones for their ability to
lyse EL-4 lymphoma cells (an H-2b tumor not infected by FMR
retroviruses) in the presence or absence of the gag peptide.
As shown for a representative CTL clone in Figure 7A, this peptide was efficient
in promoting lysis of EL-4 target cells in a dose-dependent fashion.
Furthermore, nylon wool-purified PEC isolated directly ex vivo from
M-MuLV-immune C57BL/6 mice at the peak of the response also lysed EL-4
cells in the presence of the gag peptide (Fig. 7B). Since peptide-dependent lysis of EL-4 cells by
PEC was roughly as efficient as lysis of RMA cells (a FMR+
control), our data suggest that CCLCLTVFL is a dominant epitope for
Vß5.2+V3.2+M-MuLV immune CD8+
T cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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element (V3.2) and recognize an immunodominant epitope (CCLCLTVFL)
encoded in the leader sequence of the M-MuLV gag
polyprotein. Taken together with our previous data demonstrating a
Vß10 (and to a much lesser extent V8)-restricted response to
HLA-CW3 (6, 8, 18), it is thus tempting to speculate that restricted
TCR V gene usage is a common feature of CD8+ T cell
responses to Ag in vivo. Indeed, Vß preferences also have been
demonstrated recently in CD8+ T cell responses to acute
infection by HIV (19), SIV (20), or EBV (21), and oligoclonality
appears to be a general feature of the TCR repertoire of
CD8+ (but not CD4+) cells in aged mice (22) and
humans (23). Although the structural implications of such Vß and V
preferences remain to be fully elucidated, a minimal conclusion would
be that the hypervariable CDR1 and/or CDR2 regions of the Vß and V
domains must play a role, either directly or indirectly, in the
specificity of TCR binding to peptide:MHC complexes. Indeed, the recent
resolution of the three-dimensional structure of two such trimolecular
complexes indicates that (at least in certain cases) direct contacts
between peptide residues and the CDR1 and/or CDR2 domains of the TCR
can occur (2, 3). A comparison of the phenotypic properties of Vß-restricted anti-M-MuLV or anti-HLA-CW3 cells allows certain generalizations to be made. In both systems, the responding CD8+ cells are CD62L- at the peak of the response and remain so for several months thereafter. In the response to CW3, Vß10+CD8+ cells with a CD62L+ phenotype appear very late in the response (>6 mo) (8), and these cells appear to be linealy related to the earlier Vß10+CD62L- population based on single cell PCR sequencing (24). Whether a similar evolution in CD62L expression occurs late in the CD8+ anti-M-MuLV responses described in this work is currently under investigation.
Another phenotypic feature that is shared in anti-M-MuLV and anti-CW3 systems is the down-regulation of both TCR and CD8 on the responding (CD62L-) subset of cells expressing the appropriate Vß domain. As discussed elsewhere (8), this down-regulation appears to be specific for TCR and coreceptor, since a number of other surface markers are not affected. Furthermore, cell size (as assessed by forward scatter) is very similar in both responding (CD62L-) and control (CD62L+) subsets, indicating that reduced TCR and CD8 expression is not related to decreased surface area. The functional consequences of TCR and CD8 down-regulation on immune T cells remain to be determined. Since CD8 appears to interact directly with the TCR upon ligation of peptide:MHC complexes (25, 26), one interesting possibility would be that a simultaneous reduction in TCR and CD8 density on immune cells would result in an overall increased threshold of activation. In this way, Ag-primed CD8+ T cells (already selected for a high affinity TCR) would be less susceptible to nonspecific activation by cross-reactive Ags.
Although Vß-restricted CD8+ T cell responses to M-MuLV-associated Ags share many features with the anti-CW3 response, there is at least one important difference between the two systems. Whereas Vß10+CD8+ cells are already highly enriched in DBA/2 mice 2 wk after a primary injection of viable P815-CW3 tumor transfectants, Vß-restricted anti-M-MuLV responses in either C57BL/6 or BALB/c mice are only readily detected after secondary immunization with syngeneic M-MuLV-infected tumor cells. Several explanations could account for this striking difference. First, it is possible that the frequency of CD8+ precursor cells specific for CW3 in DBA/2 mice is much higher than the anti-M-MuLV-specific precursor frequency triggered in the other strains. However, recent estimates using two independent approaches suggest that the frequency of specific precursors triggered in the CW3 model is in fact surprisingly low (15–20 per mouse) (18, 24), making it unlikely that the anti-M-MuLV precursor frequency could be much lower and still give rise to a reproducible secondary response. Alternatively, differences in the requirement for T cell help or in the expression of adhesion/costimulatory molecules by the immunizing tumor cells themselves could account for the more efficient primary response in the CW3 system. Experiments are currently in progress to attempt to distinguish among these various possibilities.
An important finding in the present study was the dramatic coexpression
of Vß5 and V3.2 on M-MuLV-specific CD8+ T cells in
C57BL/6 mice. Although T cell responses restricted by both Vß and
V domains have been demonstrated previously in vivo for the CD4
response to cytochrome c (7), our data represent (to our
knowledge) the first clear example for CD8+ cells. An
obvious practical advantage of monitoring Vß- and V-restricted T
cell responses by flow microfluorometry is that the background values
(in naive mice) are much lower than those found for responses
restricted by Vß or V alone. For example, since Vß5+
and V3.2+ cells account for 15 and 5%, respectively, of
the CD8 subset in naive mice, the threshold for detection of
Vß5+V3.2+ "double-positive" CD8 cells
in immune mice is reduced to 0.75% (assuming random association of
- and ß-chains). This threshold reduction represents a gain in
sensitivity of 10- to 20-fold compared with individual monitoring of
Vß and V domains.
In summary, our data provide strong evidence that a restricted TCR
repertoire is a common feature of CD8+ T cell responses to
physiologic Ags such as M-MuLV in vivo. In addition to their
theoretical and structural implications, these findings suggest that
Vß and/or V repertoire screening of CD8+PBL
(particularly in conjunction with an appropriate activation marker)
will prove to be an extremely useful tool in the diagnosis and
monitoring of viral infection.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. H. R. MacDonald, Ludwig Institute for Cancer Research, Ch. des Boveresses 155, 1066 Epalinges, Switzerland.
3 Abbreviations used in this paper: CDR, complementarity-determining region; CD62L, CD62 ligand; FMR, Friend/Moloney/Rauscher; MLTC, mixed lymphocyte:tumor cell culture; M-MuLV, Moloney murine leukemia virus; PEC, peritoneal exudate cell.
Received for publication June 13, 1997. Accepted for publication October 29, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T cell receptor structure at 2.5 Å and its orientation in the TCR-MHC complex. Science 274:209.-chain variable region (V3) of the mouse T cell antigen receptor. J. Immunol. 143:2602.[Abstract]
CDR1 and CDR2. Science 273:963.[Abstract]
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