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Institute for Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Freiburg, Germany;
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland;
Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, CA; and
Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RI stimulation in a basophilic leukemia cell
line (8). The inhibitory property of rat KLRG1 fits
well with its structural similarity to other members of the KLR family
that function as inhibitory receptors on NK and CD8 T cells (i.e., Ly49
and CD94/NKG2). However, attempts to demonstrate an inhibitory function
of KLRG1 on mouse NK cells have failed so far (6). To
analyze expression of KLRG1 on T cells at the protein level, we have
used a mAb specific for mouse KLRG1. We demonstrate in this study that
KLRG1 defines a subset of CD8 effector/memory T cells, which could lyse
target cells and secrete cytokines, but lost the ability to vigorously
proliferate after Ag contact. Moreover, our data show that these
senescent cells are induced in abundant numbers during viral infection
in vivo. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (B6) mice were obtained from our breeding colony or from Harlan Winkelmann (Borchen, Germany). DBA/2 mice were purchased from Harlan Olac (Bicester, U.K.). Thy1.1+ lymphocytic choriomeningitis virus (LCMV) gp33 TCR-transgenic (tg) mice (line 318) have been described (9, 10). Animals were kept under conventional conditions and were used, unless otherwise indicated, for experiments 6–16 wk after birth.
Viruses and tumors
The LCMV-WE virus strain was originally obtained from R. Zinkernagel (University Hospital Zurich, Zurich, Switzerland) and was grown on L929 fibroblast cells with a low multiplicity of infection. Vesicular stomatitis virus Indiana (VSVIND, Mudd-Summers isolate) was grown with a low multiplicity of infection on BHK cells. Stocks of vaccinia virus (VV) strain WR were produced by infecting BSC 40 cells with a low multiplicity of infection. Mice were infected (i.v.) with 200 pfu LCMV, 2 x 106 pfu VV, or 2 x 106 pfu VSVIND and were examined on day 6 (VV or VSVIND) or day 8 (LCMV) after infection. Adult DBA/2 mice were injected i.p. with 107 live P815 tumor cells transfected with the HLA-Cw3 gene (11). Two weeks thereafter, animals were bled and PBL were analyzed.
Flow cytometry
The generation of the mAb 2F1 specific for mouse KLRG1 has been
described (12) and was used as a biotinylated Ab. The
following mAbs were purchased from BD PharMingen (San Diego, CA): FITC-
and CyChrome-conjugated anti-CD8, PE-conjugated anti-CD62L,
FITC-conjugated anti-TCR V
10, and biotinylated and PE-conjugated
anti-Thy 1.1. Biotinylated mAbs were detected by
allophycocyanin-streptavidin (BD PharMingen). PE-conjugated MHC
class I (H-2Db) tetramers complexed with LCMV
gp33 peptide (13) were a kind gift of Dr. T. Dumrese
(University Hospital Zurich). Cells were analyzed on a FACSort flow
cytometer (BD Biosciences, Mountain View, CA) using CellQuest
software.
Adoptive cell transfers
Spleen cells containing 105 naive TCR-tg cells were injected (i.v.) into nonirradiated B6 mice. On the same day, recipient mice were either primed with 106 bone marrow-derived gp33 peptide-loaded dendritic cells (DCs) as described (14) or were infected with LCMV. For the cell cycling experiments, spleen cells containing 107 naive or memory TCR-tg cells were labeled with CFSE (Molecular Probes, Eugene, OR) and were injected (i.v.) into B6 recipient mice that had been infected with LCMV 3 days before. Spleen cells were isolated on day 2 (memory transfer) or day 4 (naive transfer) after transfer. TCR-tg memory cells were generated in vivo by adoptive transfer of 105 naive TCR-tg cells into B6 mice followed by infection with LCMV; they were isolated 4 wk after transfer and infection. For the repetitive transfer experiments, spleen cells containing 105 naive TCR-tg cells were injected into B6 recipient mice, followed by infection with LCMV. Thirty days after transfer and infection, spleen cells of the recipient mice containing 105 TCR-tg cells (primary memory cells) were injected a second time into B6 recipient mice, followed by infection with LCMV. The third transfer of secondary TCR-tg memory cells was performed under the same conditions.
CTL assay and IFN-
secretion
Spleen cells containing 105 TCR-tg cells
were transferred into B6 mice followed by injection of LCMV. After 8
days, spleen cells were stained with biotinylated
2F1/allophycocyanin-streptavidin and PE-conjugated anti-Thy 1.1 and
were sorted a on high speed cell sorter (MoFlo; Cytomation, Fort
Collins, CO). The cytolytic activity was determined in a 5-h
51Cr-release assay using EL-4 target cells coated
with the LCMV gp33 peptide (KAVYNFATM) or with the control adenovirus
peptide E1A234–243 (SGPSNTPPEI). For
intracellular cytokine staining, TCR-tg effector cells were cultured
for 5 h together with B6 spleen cells precoated (2 h, 37°C,
10-6 M) with gp33 peptide in medium supplemented
with brefeldin A (Golgistop; BD PharMingen). Afterward, they were
surface-stained for Thy1.1 and KLRG1, fixed, permeabilized, and stained
intracellularly using a PE-conjugated anti-IFN- mAb (BD
PharMingen).
Stimulation of TCR-tg memory cells
TCR-tg memory cells were generated in vivo by adoptive transfer of 105 TCR-tg cells into B6 mice followed by infection with LCMV; they were isolated 4 wk after transfer and infection. TCR-tg memory cells were stained with biotinylated 2F1 mAb/allophycocyanin-streptavidin and PE-conjugated anti-Thy 1.1 mAb and were sorted on a high-speed cell sorter (MoFlo; Cytomation). For the in vitro experiments, the isolated Thy1.1+ KLRG1- and Thy1.1+ KLRG1+ cells were labeled with CFSE and cultured (1.5 x 105/well) in 24-well plates together with B6 spleen cells (4 x 106/well) precoated (2 h, 37°C, 10-6 M) with LCMV gp33 peptide (KAVYNFATM). After 5 days, the cultures were harvested and the number of Thy1.1+ cells of total cultured cells and the CFSE content of Thy1.1+ cells was determined by flow cytometry. For the in vivo experiments, Thy1.1+ KLRG1- and Thy1.1+ KLRG1+ cells (105) were injected into B6 recipient mice, followed by infection with LCMV.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have used the 2F1 mAb (12) to analyze cell surface
expression of KLRG1 on CD8 T cells (Fig. 1
). KLRG1 was expressed on a small
portion (<10%) of CD8 T cells from naive C57BL/6 (B6) mice, whereas
in mice acutely infected with LCMV, more than one-half of the CD8 T
cells were KLRG1+. Analysis using MHC class I
tetramers (Db-gp33) revealed that 70–80% of CD8
T cells specific for the LCMV peptide gp33–41 expressed KLRG1 during
the acute phase of the infection (Fig. 1A,
right). Next, KLRG1 expression was examined on in vivo
activated TCR-tg CD8 T cells specific for LCMV peptide gp33–41, using
an adoptive transfer system (15). In this system,
transferred TCR-tg cells, traced by Thy1.1-specific Abs, remained below
detection limit in the recipient mice without Ag stimulation (Fig. 1B, left). Injection of LCMV gp33 peptide-coated
DCs into the recipient mice induced clonal expansion of donor TCR-tg
cells, and at the peak of expansion (day 4), 
30% of the induced
TCR-tg cells expressed KLRG1 (Fig. 1B, middle).
Clonal expansion of TCR-tg cells was more vigorous after LCMV
infection, resulting in an increased number and percentage of TCR-tg
cells that expressed KLRG1 (Fig. 1B, right).
After the acute phase of the infection, the relative number of
KLRG1+ cells in the TCR-tg population slowly
declined from 60% at the peak to 30% in the memory phase. KLRG1
expression on TCR-tg cells after LCMV infection was also observed in
spleen, lymph node, and bone marrow (Fig. 1C). To extend our
analysis to other viral systems, B6 mice acutely infected with VV or
VSV were examined. As shown in Fig. 1D, KLRG1 was induced in
30–50% of the CD8 T cells in these mice. Finally, KLRG1 expression
was determined on CD8 T cells induced by HLA-Cw3-transfected P815 tumor
cells in vivo (11). In this system, tumor cell injection
leads to expansion of tumor Ag-specific CD8 T cells predominantly
expressing TCR V10. As illustrated in Fig. 1E, KLRG1 was
expressed on 30% of TCR V10+ CD8 T cells
activated by P815/HLA-Cw3 tumor cells in vivo. Importantly, KLRG1
expression was restricted to activated T cells with down-regulated
CD62L. Taken together, these data show that KLRG1 expression was
induced in a substantial portion of CD8 T cells after stimulation by
viral and tumor Ags in vivo.
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The increased percentage of KLRG1+ TCR-tg
cells after LCMV infection, when compared with results obtained with
weaker DC/gp33 priming (Fig. 1
B), suggested a correlation
between KLRG1 expression and cell proliferation in vivo. Therefore,
KLRG1 expression was compared on activated TCR-tg cells that differed
in the number of cell cycles. For this purpose, naive TCR-tg cells were
transferred at different time points into preinfected recipient mice.
This set-up allowed variation of extent and duration of Ag exposure,
i.e., proliferation stimulus for the transferred T cells. Transfer of
TCR-tg cells into LCMV-infected recipient mice on day 1 after infection
resulted in vigorous proliferation and a high level of KLRG1 expression
(60%) on day 6 (Fig. 2A,
left). When TCR-tg cells were transferred 2 days after
infection, donor cells were already detectable on day 4 after transfer;
however, at this early time point, only 20% of the donor cells were
KLRG1+. Afterward, the number of TCR-tg cells,
and, concomitantly, the frequency of KLRG1+ cells
in the TCR-tg population increased up to 50%. Finally, KLRG1
expression remained relatively low (15%) in TCR-tg cells derived
from a 30-fold higher inoculum of TCR-tg donor cells that were
transferred on day 4 after infection, when viral titers already start
to decline (Fig. 2A, right). Taken together,
these results indicate that KLRG1 expression on naive CD8 T cells
depends on the number of cell divisions. However, it is possible that
additional factors besides cell cycling are also required for induction
of KLRG1 expression. These environmental factors could be induced by
viral infections (i.e., type 1 IFN levels) or tumor cell growth in
vivo.
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B,
left). However, KLRG1 expression was induced on only a few
(8–10%) of these cells. Two days later, the frequency of
KLRG1+ cells increased to 40–50% (Fig. 2B, left). This result indicated that the 7–9
cell divisions required to decrease the CFSE label to background levels
were not sufficient to significantly induce KLRG1 expression in naive
TCR-tg cells. This experiment was repeated using TCR-tg memory cells,
which have a replication history and therefore might be expected to
express KLRG1 after less cycles than naive cells. To trace adequate
numbers of donor TCR-tg cells early after transfer in the infected
recipient mice, higher numbers (107) of donor
cells were used for these experiments. As shown in Fig. 2C,
right, KLRG1 expression was induced in TCR-tg memory cells 2
days after transfer into LCMV-infected hosts in a cell
cycling-dependent manner. In contrast, naive TCR-tg cells transferred
under the same experimental conditions did not significantly express
KLRG1 even 4 days after transfer. Thus, memory cells "remembered"
the number of cell cycles they had undergone during the initial
expansion phase.
To provide further evidence for the cell cycling-dependent expression
of KLRG1, TCR-tg cells were repetitively stimulated by LCMV using
sequential adoptive transfer protocols. TCR-tg cells stimulated once in
vivo (primary memory cells) proliferated less vigorously than naive
TCR-tg cells after adoptive transfer and Ag stimulation. However, the
percentage of KLRG1+ cells in the donor cell
population was significantly increased in the secondary when compared
with the primary transfers, both in the acute and memory phase (Fig. 3A, left vs
middle). In tertiary transfers, TCR-tg cells that had been
stimulated twice in vivo (secondary memory cells) failed to proliferate
to detectable levels in four of six recipient mice after the third Ag
challenge. In two recipient mice, a low level of expansion of TCR-tg
cells was observed. Strikingly, KLRG1 was expressed on almost all
(>98%) of these cells, which failed to proliferate vigorously (Fig. 3A, right).
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B, bottom, the percentage of host CD8 T cells in
PBL also increased from 10% up to 40–60% in the third transfer.
Similarly, extent and kinetics of KLRG1 expression on these host CD8 T
cells were comparable in all three transfers. Thus, these data strongly
argue against the possibility that the failure of TCR-tg cells to
expand a third time was due to a more rapid viral
clearance. KLRG1+ and KLRG1- T cells do not differ in effector cell function
The adoptive transfer experiments revealed that TCR-tg
effector cells induced by LCMV infection could be divided into discrete
KLRG1+ and KLRG1-
populations (Fig. 1B, right). To correlate KLRG1
expression with functional activity, KLRG1+ and
KLRG- TCR-tg effector cells were purified by
fluorescence-activated cell sorting and were then tested for cytolytic
activity and cytokine secretion. The two cell populations exhibited
similar levels of lytic activity on EL-4 target cells coated with LCMV
gp33 peptide, and IFN- production after gp33 Ag stimulation did not
differ (Fig. 4).
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The repetitive transfer experiments shown in Fig. 3 suggested a
correlation between KLRG1 expression and reduced replicative potential.
To directly address this issue, KLRG1+ and
KLRG1- TCR-tg memory cells were purified by
fluorescence-activated cell sorting and were stimulated in vitro and in
vivo. For the in vitro experiments, KLRG1+ and
KLRG1- TCR-tg memory cells were labeled with
CFSE and were stimulated in cultures containing LCMV gp33
peptide-loaded spleen cells as APC. KLRG1-
TCR-tg memory cells (Thy1.1+) proliferated
vigorously, as indicated by an increase of
Thy1.1+ cells in the culture (Fig. 5A, left) and a
decrease in their CFSE content (Fig. 5A, right).
The proliferative potential of KLRG1+ TCR-tg
memory was reduced 10-fold and the TCR-tg cells showed strikingly
less cell divisions when compared with their
KLRG1- counterpart. The same result was obtained
when the proliferation of KLRG1+ and
KLRG1- TCR-tg memory cells was compared after
adoptive transfer and Ag challenge in vivo (Fig. 5B, left). Importantly, the transferred
KLRG1+ TCR-tg memory cells remained
KLRG1+, whereas KLRG1 expression was induced in
60% of the initially KLRG1- TCR-tg memory
cells after in vivo proliferation (Fig. 5B,
right). Taken together, these data demonstrate that
replicative senescence of Ag-stimulated CD8 T cells in vivo is
accompanied by KLRG1 expression.
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The observed link between KLRG1 expression and senescence led us
to compare the number of KLRG1+ T cells in young
and aged B6 mice that had not undergone deliberate immunization (Fig. 6). In young adult mice, only a few
(<1%) of CD4 or CD8 T cells expressed KLRG1. In mice 18–20 wk of
age, KLRG1 was found on 1.2% of CD4 and 11.4% of CD8 T cells, whereas
in 1.5-year-old mice, KLRG1 expression was further increased to 2.5%
in CD4 and 13.3% in CD8 T cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), which all express CD43 and/or CD44 at a high
level (15, 18). Our data demonstrate that KLRG1 was only expressed on T cells that had undergone a large number of cell divisions. Besides cell cycling, however, a "conditioned environment" in which T cells are stimulated may also be required for KLRG1 expression. Cytokines induced in vivo by viral infection or by tumor cell injection could represent essential factors for induction of KLRG1 expression in vivo. This notion is further supported by our failure to induce KLRG1 expression in long-term T cell cultures from TCR-tg mice stimulated weekly with Ag for 3 mo (data not shown).
The CFSE experiments shown in Fig. 2 indicate that seven to nine cell
divisions were not sufficient to induce KLRG1 expression in naive
TCR-tg cells and that KLRG1 induction in TCR-tg memory cells required
additional six to seven cell cycles. We are not aware of any other gene
induced during T cell activation that exhibits a comparable induction
kinetics. The precise number of cell cycles required for KLRG1
induction in naive T cells is unknown. After LCMV infection,
Ag-specific CD8 T cells expand 103- to
104-fold corresponding to 10–15 population
doublings (13, 15, 19). However, it is possible that
apoptosis also occurs during the expansion phase and therefore, the
actual number of population doublings of some LCMV-specific CD8 T cells
may even be higher. In addition, it is likely that proliferation of the
induced T cells is not synchronous and some T cells may proliferate
more than others. The occurrence of discrete
KLRG1+ and KLRG1-
populations among LCMV-specific T cells both in normal B6 mice and in
the transfer model supports this notion. Thus,
KLRG1+ CD8 T cells may have undergone
considerably >10–15 population doublings after LCMV stimulation
in vivo.
The increased number of KLRG1+ CD8 T cells in aged B6 mice when compared with young mice agrees well with the postulated cell division-dependent expression of KLRG1. In young adult mice, KLRG1 expression on CD4 T cells was at the detection limit and, in contrast to CD8 T cells, was also not significantly induced in the course of viral infections (data not shown). However, in aged mice a small but significant number of KLRG1+ T cells was also found in the CD4 subset. This suggests that KLRG1 can also be expressed in CD4 T cells that have undergone sufficient cell divisions. Indeed, in preliminary experiments we were able to induce KLRG1 expression in LCMV-specific CD4 T cells from SMARTA TCR-tg mice using sequential adoptive transfer protocols (data not shown). The lower frequency of KLRG1+ CD4 T cells in aged B6 mice when compared with CD8 can be readily explained by the generally observed lower clonal expansion rate of CD4 vs CD8 T cells after Ag challenge in vivo (20, 21, 22, 23, 24).
Using fetal human fibroblasts, Hayflick (25) first described that normal somatic cells have a limited replicative potential. The term replicative senescence describes the state in which cells, after having proliferated previously, are unable to further divide. To date, loss of CD28 expression is the only marker known that is associated with replicative senescence of human T cells cultured in vitro (26, 27, 28, 29). Increased frequencies of CD8+CD28- T cells have also been documented in HIV-infected individuals and in centenarians (30, 31). It will be interesting to compare KLRG1 up- vs CD28 down-regulation on human CD8 T cells during aging and also in clinical situations, such as viral infections, which are associated with massive proliferation (i.e., EBV) or exhaustive differentiation (i.e., HIV) of CD8 T cells. In the mouse, loss of CD28 expression cannot be used as a marker for replicative senescence because CD28 is barely detectable even on unstimulated CD8 T cells. Thus, KLRG1 represents the first and so far only maker available to identify senescent murine T cells in vivo. The present report raises the intriguing question whether inhibitory signals mediated by KLRG1 are responsible for the impaired proliferation rate of KLRG1+ T cells. Further work using KLRG1-transgenic and KLRG1-deficient mice will help to clarify this interesting issue.
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Acknowledgments |
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Footnotes |
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2 Current address: Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.
3 Current address: Immunex Corporation, Seattle, WA 98101.
4 Address correspondence and reprint requests to Dr. Hanspeter Pircher, Institute for Medical Microbiology and Hygiene, Department Immunology, University of Freiburg, Hermann-Herder-Strasse 11, D-79104 Freiburg, Germany. E-mail address: pircher{at}UKL.uni-freiburg.de
5 Abbreviations used in this paper: KLR, killer cell lectin-like receptor; KLR member G1, KLRG1; LCMV, lymphocytic choriomeningitis virus; VSVIND, vesicular stomatitis virus Indiana; VV, vaccinia virus; DC, dendritic cell; tg, transgenic.
Received for publication April 5, 2001. Accepted for publication August 20, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cell repertoire due to different clonal expansions in the CD4+ and CD8+ subsets. Int. Immunol. 10:1281.This article has been cited by other articles:
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Y. Hayakawa and M. J. Smyth CD27 Dissects Mature NK Cells into Two Subsets with Distinct Responsiveness and Migratory Capacity J. Immunol., February 1, 2006; 176(3): 1517 - 1 |
) was determined at the indicated time points. D,
KLRG1 expression on CD8 T cells from B6 mice acutely infected with VV or VSV. PBL were stained 6
days after infection with anti-CD8 and anti-KLRG1 mAb.
E, KLRG1 expression on CD8 T cells stimulated by tumor
cells in vivo. DBA/2 mice were injected i.p. with live P815 tumor cells
transfected with the HLA-Cw3 gene (
