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J Virol, January 1998, p. 726-730, Vol. 72, No. 1
Departments of Medicine,
Received 18 March 1997/Accepted 16 October 1997
The integrin Subsets of memory lymphocytes and
immunoblasts display tissue-selective homing and recirculation (7,
9, 10, 19, 29, 37). These homing preferences are thought to
reflect differential interaction of lymphocytes with specialized
vascular endothelium mediated by differential expression of homing
receptors on the surfaces of circulating memory/effector cells (6,
8, 9, 29, 37). The integrin Rotavirus is a segmented, double-stranded RNA virus of the family
Reoviridae and is a major pathogen of the intestinal tract (15). Rotavirus infection occurs in, and is largely limited to, the villus enterocytes of the small intestine (18). The specificity of viral replication ensures that the immunologic response
to rotavirus is focused in the intestinal compartment. In both neonatal
and adult mice, large amounts of rotavirus-specific immunoglobulin A
(IgA) are found in stool samples following virus clearance and persist
for up to 1 year following primary infection (5, 33).
Virus-specific CD8+ cytotoxic T lymphocytes (CTLs) are
detected at the intestinal surface following acute infection
(36), and passively transferred CTLs can both protect
suckling mice against diarrhea (34) and migrate to the
intestinal surface to clear chronic rotavirus infection in severe
combined immunodeficiency mice (12) and Rag-2 mice (17). Rotavirus-specific CTLs are detected in mucosal nodes (PP and mesenteric lymph nodes [MLN]) early in infection and are later detected in the spleen, presumably after encountering rotavirus in the gut (35). Recently, we and others have shown that
CD8+ T cells play an important role in the timely
resolution of primary rotavirus infection and a much lesser role in
protection from reinfection (16, 17, 32, 34).
To test the hypothesis that expression of the mucosal integrin
Mice, viruses, and viral inoculation.
Stocks of wild-type
murine EC rotavirus were prepared as intestinal homogenates, and their
titers were determined in mice as previously described (5).
Stocks of tissue culture-adapted rhesus rotavirus (RRV) were prepared
as previously described (22). Six-week-old C57BL/6 mice were
obtained from the Charles River Laboratory (Hollister, Calif.) and bred
in the Palo Alto Veteran's Administration breeding facility to be used
as donors for cell transfer experiments. Prior to study, we showed by
enzyme-linked immunosorbent assay (ELISA) that the serum of mice used
in these experiments was negative for rotavirus antibody. Mice were
orally gavaged with 105 50% diarrheal doses
(DD50) of virus after receiving 100 µl of 1.33% sodium
bicarbonate to neutralize stomach acid. Viral shedding was monitored by
ELISA to assess the progress of infection (5). One month
following the initial infection, immunized mice were boosted by gavage
with a second dose of virus (105 DD50).
Splenocytes from donor mice were harvested for sorting experiments
between 3 and 12 weeks after boosting. (Due to the extremely low number
of rotavirus-responsive cells, we were unable to assay cytotoxicity in
vitro; however, we inferred that there was no significant difference in
cells harvested 3 versus 12 weeks after boosting, as we have shown that
CD8+ T cells can mediate partial long-term protection for
up to 5 months after viral reinfection [17]. Also,
shedding of rotavirus in JHD Detection of viral antigen.
Viral antigen detection was
performed by ELISA as described previously (5). Briefly,
microtiter plates (Dynatech, McLean, Va.) were coated with diluted
hyperimmune guinea pig anti-RRV serum and blocked with 5% nonfat dry
milk. Stool samples were made to a 10% suspension, added to plates,
and incubated for 2 h at 37°C. Antigen was detected with rabbit
anti-RRV serum, followed by horseradish peroxidase (HRP)-conjugated
goat anti-rabbit serum (Kirkegaard & Perry Laboratories, Gaithersburg,
Md.). Visualization was performed by incubation of plates with ABTS
{2,2'-azino-di[3-ethylbenzthiazoline sulfonate (6)]}
substrate (Kirkegaard & Perry), and then the reaction was quenched with
10% sodium dodecyl sulfate. Plates were read by using an EIA
Autoreader (BIO-TEK Instruments, Burlington, Vt.) at 405 nm. Clearance
was defined as the point at which ELISA values fell below an optical
density (OD) of 0.08. To determine the background absorbance levels,
stool samples from mice that had not been infected with rotavirus (OD,
Antibodies and reagents.
For sorting, a biotinylated
monoclonal antibody (MAb) to CD8 (Lyt2) and a phycoerythrin
(PE)-conjugated MAb to Staining and cell sorting.
Splenocytes to be sorted from
donor rotavirus-infected C57BL/6 mice were harvested, disaggregated by
teasing between glass slides, and pressed through stainless steel
screen mesh (0.0021-in. diameter). Pooled cells were washed with 5 to
10 ml of Dulbecco's modified Eagle's medium supplemented with 10%
fetal bovine serum (DMEM-10) and then treated with 5 ml of lysis buffer
(0.15 M NH4Cl, 1 mM KHCO3, 0.1 mM
Na2EDTA) for 5 min to lyse erythrocytes. After lysis,
splenocytes were washed twice and resuspended in DMEM-10. The yield was
typically 1 × 108 to 2 × 108 cells
per harvested spleen. Splenocytes to be sorted were enriched for
CD8+ T cells by panning on plates coated with anti-CD4 and
anti-B220 antibodies, as previously described (17). Panned
cells were resuspended in DMEM-10.
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Expression of the Mucosal Homing Receptor
4
7 Correlates with the Ability of
CD8+ Memory T Cells To Clear Rotavirus Infection
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
4
7 plays an important
role in lymphocyte homing to mucosal lymphoid tissues and has been
shown to define a subpopulation of memory T cells capable of homing to
intestinal sites. Here we have used a well-characterized intestinal
virus, murine rotavirus, to investigate whether memory/effector
function for an intestinal pathogen is associated with
47 expression. 47hi memory phenotype
(CD44hi), 47
memory phenotype, and presumptively naive (CD44lo)
CD8+ T lymphocytes from rotavirus-infected mice were sorted
and transferred into Rag-2 (T- and B-cell-deficient) recipients that
were chronically infected with murine rotavirus.
47hi memory phenotype
CD8+ cells were highly efficient at clearing rotavirus
infection, 47 memory cells
were inefficient or ineffective, depending on the cell numbers
transferred, and CD44lo cells were completely unable to
clear chronic rotavirus infection. These data demonstrate that
functional memory for rotavirus resides primarily in memory phenotype
cells that display the mucosal homing receptor
47.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
47, for
example, mediates lymphocyte recognition of the mucosal vascular
addressin (MAdCAM-1) (4, 21) and is involved in lymphocyte
homing to Peyer's patches (PP) and intestinal lamina propria (2,
4, 20, 31). Importantly, previously activated/memory T
lymphocytes are subdivided into discrete
47hi and
47 populations (1, 13,
42) with distinctive patterns of MAdCAM-1 binding
(39), recirculation (30), and homing
(44). In particular, memory/effector cells expressing high
levels of 47 home to intestinal PP and
recirculate through intestinal tissues, whereas those that do not
express 47 are virtually excluded. Such
observations of differential 47
expression and homing properties of circulating memory T-cell subsets
have led to the hypothesis that
47+ memory cells may comprise
cellular memory to mucosal antigens. However, this hypothesis has not
been tested and the selective ability of such memory cells to exert a
specific effector function at a mucosal surface has not been directly
demonstrated.
47 might correlate with and function in
defining memory for mucosa-restricted antigens, we sorted
CD8+ T-cell subsets from C57BL/6 mice which had previously
been infected with murine rotavirus. The
47hi CD44hi,
47 CD44hi, and
CD44lo subsets were transferred (separately) into Rag-2
(43) (T- and B-cell-deficient) recipients chronically
infected with murine rotavirus, and viral clearance was monitored. We
show that the 47hi
CD44hi subset selectively clears rotavirus and that the
ability to clear rotavirus is either rare or absent in the
47 CD44hi or
presumptively naive (CD44lo) subsets of CD8+ T
cells. These results demonstrate for the first time that functional memory for a mucosal pathogen resides primarily in memory phenotype cells that display the mucosal homing receptor
47.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
/ mice
challenged with rotavirus is the same 6 and 12 weeks after inoculation
[32]. Recipient Rag-2 mice (43) were
obtained from Taconic (Germantown, N.Y.) and infected with
105 DD50 of the murine EC virus as previously
described (16). Stool samples from infected mice were
assayed for viral antigen at 2 weeks postinoculation to confirm the
establishment of chronic infection. Rag-2 mice were chronically
infected for 1 to 3 months prior to cell transfer.
0.08), in addition to wells with no stool sample (OD, 0.04), were
assayed by ELISA. Also, samples were assayed in the absence of rabbit
anti-RRV serum (OD, 0.04), in the absence of HRP-conjugated goat
anti-rabbit serum (OD, 0.05), and in sample wells not coated with
guinea pig anti-RRV serum (OD, 
0.05 to 0.06).
47 (DATK32) were
purchased from PharMingen, La Jolla, Calif. A fluorescein isothiocyanate-conjugated MAb to CD44 (MJ64) (3) was
produced and conjugated in the laboratory of E. C. Butcher. A
biotinylated MAb to human CD44 (Hermes-1) (23), produced in
the laboratory of E. C. Butcher, and PE-conjugated anti-rat-IgG2a
(PharMingen) were used as isotype control antibodies. Streptavidin-Red
613 (Red 613) was purchased from GIBCO (Gaithersburg, Md.). Ascites containing antibodies against CD4 (GK1.4) and B220 (RA36B2), used for
subtractive panning, was produced in the laboratory of E. C. Butcher.
47 (DATK32;
0.09 µg/106 cells), and CD44 (MJ64; 1:150 dilution).
Cells were incubated on ice for 20 min with MAbs in 300 µl of DMEM-10
and then washed at 4°C with 3 ml of DMEM-10. Splenocytes were then
stained with Red 613 (0.5 µl/106 cells) for 20 min on
ice, washed with 3 ml of DMEM-10, and resuspended in DMEM-10 for
sorting.
47 memory
CD8+ and naive CD8+ populations were sorted
twice to optimize purity. The level of purity after sorting once (98.7% ± 1.3%) was determined by using the FACStar. Because of the
scarcity of cells, the purity of the transferred cells that had been
sorted twice could not be determined; however, in parallel experiments,
we determined by FACStar analysis that the purity after sorting twice
was typically at least 99.7%. Double sorting of CD8+ cells
has no effect on the efficiency of CD8+ T-cell-mediated
rotavirus clearance (17). Approximately 20,000 47hi CD44hi
(single-sorted) and 47
CD44hi (double-sorted) cells were obtained from an input of
7 × 107 panned (depleted of B220+ and
CD4+ cells) splenocytes. Sorted donor cells were
resuspended in sterile saline solution at 105/ml and
injected intraperitoneally into chronically infected Rag-2 mice.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
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Splenic CD8+ lymphocytes can be partitioned into three
distinct populations.
Figure 1 shows
a representative fluorescence-activated cell sorter (FACS) plot of
gated small CD8+ splenocytes from rotavirus-immunized mice.
Cells were stained with MAbs to CD44 and the mucosal homing receptor
47. We used CD44 as a marker for
memory/effector T cells, as an increase in CD44 expression correlates
with memory/effector function in certain strains of mice, including
C57BL/6 (14, 28). We selectively analyzed small lymphocytes
(as opposed to blasts) by gating on cells with decreased forward
scatter intensity (compared to the higher intrinsic forward scatter of
blasts). Three distinct populations can be identified in the plot:
47hi memory
(CD44hi), 47
memory (CD44hi), and
47lo naive
(CD44lo to CD44). No significant differences
were observed in staining patterns between naive mice and mice
immunized with rotavirus (data not shown), and the subsets identified
in Fig. 1 represent 4% (47hi
memory phenotype), 28% (47
memory phenotype), and 66% (naive) of the total CD8+
population. Sort gates were established to select the brightest of the
47hi memory phenotype cells
(2% of the total CD8+ cells), the most weakly staining
47 memory phenotype cells
(6% of the total CD8+ cells), and naive-phenotype cells
comprising the population staining at low levels for CD44 (30% of the
total CD8+ cells) (Fig. 1). We sorted cells from the
spleen, an organ that efficiently recruits both
47hi and
47 memory cells from the
blood (44), to obtain significant numbers of all three
populations.
|
CD8+ T cells expressing high levels of
47 and CD44 clear rotavirus
infection.
Splenocytes were stained with CD44 to identify
previously activated (presumptive memory) lymphocytes (14,
28) among the 47hi and
47 cells. When 20,000 47hi memory cells
(CD44hi) were transferred into recipients, viral clearance
occurred in 4 to 5 days (Table 1). Naive
(CD44lo) CD8+ cells derived from
rotavirus-immunized mice were unable to clear the virus. Antigen
shedding in recipients of naive CD8+ cells continued for up
to 3 months, when the experiment was terminated. When 20,000 47 CD44hi cells
were transferred, mice cleared the virus, although only after a
substantial delay (16 days; 11 to 12 days longer than 47hi cells) (Table 1).
|
47 cells could be due to
small numbers of 47hi cells
which were not removed during the sorting (
99.7% purity). These
cells could undergo proliferation and expansion after transfer, thereby
clearing the virus after an initial lag phase. We reasoned that
transfer of limiting numbers of cells should reduce or eliminate the
lymphocytes capable of clearing virus from the
47-treated mice. To test
this hypothesis, we conducted a series of experiments in which 10,000 cells of each phenotype were transferred. When 10,000 sorted cells were
transferred, neither mice receiving CD44lo cells nor mice
receiving 47
CD44hi cells were able to clear the virus, even 60 days
after cell transfer (when the experiment was terminated) (Table 1; Fig.
2). In contrast, all mice receiving
10,000 47hi
CD44hi CD8+ cells cleared the virus within 16 to 17 days.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Our results indicate dramatic differences between the abilities of
naive, 47hi memory, and
47 memory CD8+
spleen cells to clear chronic rotavirus infection after passive transfer. Only the populations of CD8+ cells expressing
high levels of the 47 integrin and the
CD44 memory marker were able to clear rotavirus in limiting-dilution assays. Naive (CD44lo) CD8+ cells were unable
to clear the virus after transfer into infected Rag-2 mice, an
observation consistent with the reported requirement for
CD4+ T-cell help during primary CTL responses to some
rotaviral infections (16a). Elimination of rotavirus by
47 cells was significantly
delayed at all cell doses and was observed only when 20,000 cells were
transferred.
The kinetics of clearance by transferred memory cells was dependent on
cell number, as demonstrated by the difference between the clearance
rates obtained by using different protocols (Table 1), as well as CD44
expression (n = 2; data not shown). Transfer of 20,000 47hi CD44hi cells
resulted in significantly faster clearance than transfer of 10,000 47hi CD44hi
cells. The delay in clearance following transfer of limiting cell
numbers may be attributed to the expansion of a small number of
rotavirus-specific T cells to a population size adequate for elimination of the virus.
47 cells were unable to
clear the virus even at later time points when transferred at 10,000 cells/recipient. Although we cannot formally exclude the possibility of
the existence of 47
rotavirus-specific CD8+ cells (whose efficiency in clearing
virus might be compromised by inefficient access to the mucosal lamina
propria
see below) in these in vivo studies, the complete inability of
10,000 47 CD8+
cells to eliminate the virus even after 60 days demonstrates that
functional memory for this intestinal viral pathogen is comprised of
47hi cells and suggests that
this inability reflects segregation of rotavirus-specific
CD8+ effector cells into the
47hi subset during the
intestinal immune response.
While it appears that effective memory for rotavirus resides primarily
among 47hi CD44hi
CD8+ cells, rotavirus-specific cells may not be exclusively
in this subset. Transfer of 20,000 47 CD44hi
CD8+ cells resulted in clearance, although with much slower
kinetics than clearance by
47hi CD44hi
CD8+ cells. Delayed clearance by the
47 population could be due
in part to inefficient access to the mucosa in the absence of this
intestinal homing receptor. In this scenario,
47 effector cells might
acquire 47 after transfer, thus
explaining the delay in clearance. The malleability of homing receptor
expression has not been established, but in parallel preliminary
experiments in which double-sorted
47CD44hi
CD8+ cells were transferred into Rag-2 mice chronically
infected with rotavirus, we observed a low but significant percentage
of 47hi cells (~3 to 10%
of gated CD8+ small lymphocytes) in the spleens and MLN of
animals that had cleared the virus, with slightly fewer (~2 to 5%)
in animals which had not cleared the virus. On the other hand, as
discussed above, clearance by the sorted
47 population may be due to
a small percentage of contaminating 47hi cells (estimated as
<0.03%), which are unavoidable during the sorting procedure.
Infection of mice with viruses which replicate in mucosal tissues leads to an immune response that is targeted to mucosal sites. Studies of the development of the immune response to rotavirus have shown the rapid appearance of virus-specific CTLs in the PP and MLN after infection (36). Likewise, infection with reovirus, another mucosa-specific virus, leads to an enrichment of virus-reactive CTLs in the intestinal intraepithelial lymphocytes and PP (11, 16, 17, 25, 26), as well as an increase in the frequency of virus-specific B cells and CD4+ T cells in PP as opposed to peripheral lymph nodes (27). The enrichment of virus-reactive cells in mucosal versus nonmucosal compartments suggests a mechanism by which these cells are directed to mucosal compartments.
Previous and concurrent studies have examined the segregation of memory
for regional immune responses into homing receptor-defined subsets of
CD4+ cells or of antibody-producing B effector or effector
precursor cells. In studies of human CD4+ proliferative
responses, for example, we have found that rotavirus-specific memory
following natural infection segregates selectively to the 47hi CD4+ cells,
whereas proliferative CD4+ cells responding to
intramuscular mumps vaccine are largely
47 (40). Human
CD4+ T cells responsive to nickel and dust mite cutaneous
antigens involved in allergic dermatitis are enriched among cells
displaying the cutaneous lymphocyte antigen skin-homing receptor
(41), a population that, in contrast to intestinal
rotavirus-reactive cells, lacks the mucosal homing receptor
47 (39). Furthermore, a
humoral, as well as a CD8-mediated, cellular immune response can also
clear chronic rotavirus infection in the immunodeficient mouse model,
and ongoing studies have revealed compartmentalization of
rotavirus-specific B-cell responses, with the
47hi memory phenotype subset
selectively clearing the virus and secreting rotavirus-specific,
stool-localized IgA (43a). Finally, our findings here are
consistent with recent studies of antigen-specific antibody-secreting cells induced by gastrointestinal versus systemic immunization with
defined antigens, which resulted in enrichment or depletion of
47 expression, respectively (23, 24,
38). The expression of 47 by
functional immune cells for mucosal pathogens may have important
implications for vaccine development and suggests that the efficiency
of generation of 47+ (versus
47) memory may correlate
with functional gastrointestinal immunity.
In conclusion, our findings confirm that memory CD8+ cells,
like their CD4+ counterparts, can be subdivided based on
differential homing receptor expression (13, 39),
demonstrate that functional memory for rotavirus resides primarily in
memory phenotype cells that display the mucosal homing receptor
47, and support the importance of
differential homing receptor expression in the compartmentalization of
immune responses.
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ACKNOWLEDGMENTS |
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J. R. Rosé and M. B. Williams contributed equally to this report, and H. B. Greenberg and E. C. Butcher contributed equally as senior authors.
This research was supported by Microbiology and Immunology training grant 5T32AI07328-09 (J.R.R.), NIH National Research Service Award AI08872 from the National Institute of Allergy and Infectious Diseases (M.B.W.), the FACS Core Facility of the Stanford Digestive Disease Center under grant DK38707 (L.S.R.), NIH grant AI37832 (E.C.B.), NIH grant R37 AI21362 (H.B.G.), and V. A. Medical Investigator Awards from the Department of Veterans Affairs Palo Alto Health Care System (E.C.B. and H.B.G.).
We thank members of the Butcher and Greenberg laboratories for illuminating discussions, especially M. Franco.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Pathology, L235, Stanford University School of Medicine, Stanford, CA 94305-5487. Phone: (650) 493-5000, ext. 6-3122 (J. R. Rosé) or 6-3134 (M. B. Williams). Fax: (650) 852-3259 (J. R. Rosé) or (650) 858-3986 (M. B. Williams).
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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J Virol, January 1998, p. 726-730, Vol. 72, No. 1
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Copyright © 1998, American Society for Microbiology. All rights reserved.
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