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, and IL-10 Regulation1
Department of Basic Sciences, Dental Branch, University of Texas Health Science Center, Houston, TX 77030
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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staining. However, OX40 and OX40L expression were rapidly
up-regulated on CD8 IELs following CD3 stimulation, indicating that
both markers on IELs reflect activation-dependent events. Unlike IELs,
activated lymph node T cells did not express OX40L, thus indicating
that OX40-OX40L communication in the intestinal epithelium is part of a
novel CD8 network. Functionally, OX40 expression was exclusively
associated with IELs with active intracellular IFN- synthesis and
markedly enhanced cell-mediated cytotoxicity. However, OX40
costimulation during CD3-mediated activation significantly suppressed
IL-10 synthesis by IELs, whereas blockade of OX40-OX40L by
anti-OX40L mAb markedly increased IL-10 production. These findings
indicate that: 1) resident CD69+OX40- IELs
constitute a population of partially activated T cells poised for rapid
delivery of effector activity, 2) OX40 and OX40L expression defines
IELs that have undergone recent immune activation, 3) OX40+
IELs are significantly more efficient CTL than are OX40-
IELs, and 4) the local OX40/OX40L system plays a critical role in
regulating the magnitude of cytokine responses in the gut
epithelium. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(2, 3, 4, 5, 6). That the latter is a true property of
murine IELs is supported by multiple lines of evidence. First, ex vivo
cytolytic activity of IELs in short-term 2- to 4-h cultures has been
independently reported by a number of laboratories (2, 3, 4, 5, 6).
Second, this activity cannot be attributed to cell isolation
methodologies given that peripheral splenic or lymph node T cells
exposed to the IEL extraction protocol do not acquire cytotoxic
activity or CD69 expression, and because IELs isolated by mechanical
disruption without enzyme digestion retain cytotoxic activity (our
unpublished observations). Third, in situ activation of IELs is
dependent upon the presence of luminal Ags as seen in studies in which
germ-free mice express little lytic activity, whereas mice housed under
conventional conditions are cytotoxic (6), thus suggesting
that the intestinal microenvironment conditions the functional response
of resident lymphocytes. OX40 was first identified as an activation molecule on rat lymphocytes (7). An equivalent molecule for mouse T cells has been recently described and, although originally linked to the activation of CD4 T cells, it is now clear that mouse CD8 T cells activated either by CD3 cross-linking or by lectin stimulation also express OX40 (8, 9, 10). The ligand for OX40 (OX40L) is expressed at varying levels on B cells, T cells, and APCs including dendritic cells (DCs) (11, 12, 13). Although OX40L can be constitutively expressed at low levels on those cells, its expression is increased during activation (14, 15), thus accounting for the costimulatory properties of OX40L-mediated lymphocyte stimulation (12, 13, 16, 17).
Recently, OX40 has been implicated in human intestinal inflammatory responses as seen by increases in OX40 expression in the intestine of patients with inflammatory bowel disease (18) and in patients with active celiac disease, Crohn’s disease, and ulcerative colitis (19). However, those studies did not establish whether OX40 expression is a function-associated characteristic of cells undergoing local activation thus directly linking OX40 to the inflammatory process itself, or whether expression is acquired as a secondary or ancillary event of inflammation. Circumstantial evidence favoring the former comes from studies of graft-vs-host disease in mice in which OX40 expression is up-regulated on T cells in secondary lymphoid tissues before the onset of intestinal tissue destruction (20). At present, little else is known about the expression of OX40 and IEL activation in mice.
To better understand the stages involved in IEL activation, we have examined the expression of OX40 and OX40L on IELs in freshly isolated cell preparations and in in vitro CD3-stimulated cultures. These findings indicate that unlike T cells in other peripheral immune compartments, small intestine IELs exist in differential states of activation, and they define a mechanistic role for OX40 in the generation and regulation of local immunity. A model for OX40 involvement in intestinal immunity and immunopathology is presented.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Adult female BALB/c and C57BL/6 mice, 8–12 wk of age, were purchased from Harlan Sprague-Dawley (Houston, TX) and were maintained at the University of Texas (Houston, TX) vivarium. Animals were housed and used under conditions approved by the University of Texas Animal Welfare Committee.
Lymphoid cell isolations
Small intestine tissues were removed and Peyer’s patches were dissected out. Tissues were flushed of fecal material, opened longitudinally, and cut into 3- to 4-mm pieces in RPMI 1640 supplemented with FCS (10% v/v), 100 U/ml penicillin-streptomycin, 2 mM L-glutamine, and 5 x 10-5 M 2-ME (all from Sigma-Aldrich, St. Louis, MO). Tissue fragments were rinsed several times in Ca2+/Mg2+-free PBS and stirred at 37°C for 30 min in Ca2+/Mg2+-free PBS containing 5 mM EDTA and 2 mM DTT (Sigma-Aldrich). Cells were filtered successively through three 10-cc syringe barrels containing wetted nylon wool, centrifuged, suspended in 3 ml of 40% isotonic Percoll (Sigma-Aldrich), layered on top of 70% isotonic Percoll, and centrifuged for 20 min at 600 x g. IELs were recovered from the Percoll interface. In some cases, the Percoll step was repeated. Based on expression of the leukocyte common Ag (LCA), CD45, by flow cytometry, 85–92% of the cells were IELs, with >98% viability by trypan blue exclusion. Mesenteric lymph node cells were obtained by pressing tissues through a 60-mesh stainless steel screen.
Abs and flow cytometry
Abs used in this study were purified anti-CD3
(145-2C11), FITC-anti-CD8
(53-6.7), FITC-anti-CD8
(53-5.8),
FITC-anti-CD45 LCA (30-F11), PE-anti-CD69 (H1.2F3),
biotin-anti-CD134/OX40 (OX86), biotin-anti-OX40L (RM134L), purified
anti-OX40L (RM134L (NA/LE)), anti-hamster (G94-56), purified
hamster Ig, purified rat IgG (R35-95), propidium iodide,
streptavidin-CyChrome, anti-CD16/32 Fc block (2.4G2) (all from BD
PharMingen, San Diego, CA); and anti-rat IgG/M (312-005-044)
(Jackson ImmunoResearch Laboratories, West Grove, PA). Intracellular
IFN- staining was done using a commercial cell staining kit (BD
PharMingen) with the manufacturer’s reagents, protocols, and controls.
Stained cells were analyzed on a FACSCalibur flow cytometer using
CellQuest software (BD Biosciences, San Jose, CA). Background staining
by species-matched control reagents is demarcated by the position of
cells in the lower left histogram quadrant.
Cell culture
For flow cytometric analyses, purified IELs were cultured at a density of 1.2–2.0 x 106 cells/2 ml in 24-well plates coated with anti-CD3 mAb or in uncoated or control mAb-coated wells with supplemented RPMI 1640 (as described above) in the presence or absence of rIL-2 and/or rIL-15 (Sigma-Aldrich). In some initial experiments, wells were coated overnight by direct binding of anti-CD3 (145-2C11) mAb or isotype-matched hamster control mAb to plates. However, in most experiments, CD3 stimulation was done by coating wells overnight at 4°C with 10 µg/ml anti-hamster mAb, washed with PBS, and incubated for 1 h at 37°C with mAb 145-2C11. Unbound Ab was removed by washing before the addition of cells. For CD3/OX40 costimulation, wells were coated overnight at 4°C with a suspension of 10 µg/ml anti-hamster mAb and 10 µg/ml anti-rat mAb. Wells were washed with PBS and incubated for 1 h at 37°C with 5 µg/ml mAb 145-2C11 and 5 µg/ml anti-OX40 mAb. For soluble blockade using anti-OX40L mAb, wells were coated overnight at 4°C with 10 µg/ml anti-hamster mAb, washed with PBS, incubated for 1 h at 37°C with 5 µg/ml mAb 145-2C11, and washed, and cells were added with the indicated amount of soluble anti-OX40L mAb. Cells were collected after 24 or 48 h, stained, and analyzed by flow cytometry after gating onto viable cells using propidium iodide exclusion, or supernatants were recovered for cytokine assays. For determination of cytokine-mediated cell survival, viability was scored at 24 and 48 h by trypan blue exclusion. For in vitro stimulation of lymph node cells, 15 x 106 mesenteric lymph node cells were cultured in 5 ml of supplemented RPMI 1640 in 60-mm petri dishes coated with anti-hamster mAb followed by mAb 145-2C11 as described above.
Cytotoxicity and cytokine assays
Redirected cytotoxicity assays were done as previously reported (3), except that Fc-receptor-bearing C26 tumor target cells were used. For analyses of redirected cytotoxicity from CD3-stimulated in vitro cultures, IELs were collected and dead cells were removed by centrifugation through a 40%/70% Percoll gradient. Cells at the interface were collected, washed, and separated into OX40+ and OX40- populations by magnetic-activated cell sorting (Miltenyi Biotec, Auburn, CA). In brief, IELs were reacted for 10 min at 4°C with purified anti-OX40 mAb, washed, and reacted for 15 min at 4°C with anti-rat Ig microbeads (Miltenyi Biotec). Cells were washed, resuspended in PBS containing 2 mM EDTA and 0.5% BSA, and added to the magnetic column. The nonattached OX40- fraction was collected by washing the column with wash buffer; OX40+ cells were collected after detachment of the magnetic column. OX40+ and OX40- effector cells were adjusted to the same concentration and assayed for lytic activity in a 4-h redirected cytotoxicity assay.
For analyses of IL-2, IL-4, IL-10, and IFN- cytokine activity,
1 x 106 IELs were cultured for 24 h as
described above in rIL-15-supplemented medium (rIL-2 was omitted
to permit measurement of IL-2 activity). Cell-free supernatants were
collected and assayed for cytokine activity with a commercial
immunoassay kits (eBiosience, San Diego, CA) using the
manufacturer’s protocols and standards.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Freshly isolated IELs were stained for CD69, OX40, and
intracellular IFN- expression and were assayed for evidence of
activation in the redirected cytotoxic assay. As shown in Fig. 1
, >98% of CD8+
IELs were CD69+; in the presence but not in
absence of anti-CD3 mAb, those cells were cytotoxic for FcR-bearing
target cells. However, interestingly, despite that evidence of
activation, CD8+ IELs were
OX40- and OX40L- and did
not stain for intracellular IFN- (Fig. 1). These were consistent
findings from BALB/c and C57BL/6 mice. To understand how OX40
expression relates to the process of T cell activation, lymph node
cells were activated in vitro by CD3 stimulation. These studies
demonstrated that CD69 and OX40 expression are acquired at different
times during activation. Note that between 24 and 48 h only
16–17% of CD8+ lymph node T cells expressed
OX40, whereas 57–61% were CD69+, and that OX40
was not maximally expressed until 72 h poststimulation (Fig. 2), a finding also reported by others for
OX40 (10). These findings thus indicate that during immune
activation it is possible to have a population of CD8 T cells that are
CD69+ but OX40-, similar
to freshly isolated IELs (Fig. 1).
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We sought to determine the conditions that favor terminal
activation of IELs. Freshly isolated IELs were cultured in vitro with
or without CD3 stimulation in the presence of IL-2 and IL-15. IL-15 is
known to promote the survival of IELs, particularly though not
exclusively for CD8 cells, whereas IL-2 is required as a
growth factor for IELs following TCR/CD3 stimulation (21, 22). Optimal concentrations of rIL-15 for these experiments were
determined by measuring the viability of non-CD3-stimulated IELs after
24 h of culture. Similar to what has been reported by others
(21), 50–200 ng/ml of rIL-15 significantly enhanced IEL
viability compared with cultures without IL-15 (data not shown).
Viability was also determined for IELs at 24 and 48 h in the
presence of 4 ng/ml rIL-2, a concentration previously used for in vitro
IEL culture experiments (21), with and without rIL-15.
Viability of IELs remained high (85–90%) when cultured in the
presence of rIL-15. The presence of rIL-2 in those cultures did not
alter viability, though viability was reduced slightly in cultures
containing rIL-2 alone (data not shown). Concentrations of 4 ng/ml
rIL-2 and 100 ng/ml rIL-15 were therefore used in subsequent
experiments.
Expression of OX40 and OX40L on IELs was evaluated after 24 and 48
h of culture with rIL-2 and rIL-15 in the presence or absence of CD3
stimulation. Non-CD3-stimulated IELs (or IELs cultured with
isotype-matched hamster mAb) cultured for 24 h retained levels of
OX40 expression (Fig. 3A) that
were only slightly higher than those of freshly isolated cells (Fig. 1
). Similar findings were observed for OX40L expression in
non-CD3-stimulated cultures (data not shown). In contrast, a
significant proportion of CD3-stimulated IELs expressed OX40 and OX40L
at 24 h; this consisted of a population of
CD8+OX40high cells and
CD8+OX40Lhigh cells, and a
population of CD8+OX40low
cells and CD8+OX40Llow
cells that appear to be in the process of acquiring OX40 and OX40L
expression (Fig. 3, C and E). The patterns
observed at 24 h were retained and extended in 48-h cultures in
that nearly all CD8+ cells cultured with rIL-2
and rIL-15 without CD3 stimulation were OX40-
and OX40L- (Fig. 3B), whereas 98% of
CD8+ cells acquired OX40 expression and 89% of
the CD8+ cells acquired OX40L in 48-h
CD3-stimulated cultures (Fig. 3, D and F).
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A, nearly all
OX40+ and OX40L+ cells were
LCA+. Moreover, OX40 and OX40L expression
occurred on both CD8 and CD8 cells (Fig. 4B).
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The above findings suggest that OX40-OX40L communication in the
gut epithelium takes place between CD8 T cells during activation. To
determine whether OX40L expression is a feature of T cell activation
that is unique to the gut, and whether the activation conditions used
for IELs might have affected the expression of those markers, lymph
node T cells were cultured under identical conditions of CD3
stimulation and rIL-2 and rIL-15 culture used for IELs. At both 24
(Fig. 5, A and C)
and 48 (Fig. 5, E and G) h there was no
significant increase in OX40L expression on lymph node T cells
following CD3 stimulation. T cells cultured with rIL-1 and rIL-15 in
the absence of CD3 stimulation also failed to express OX40L at 24 (Fig. 5, B and D) and 48 (Fig. 5, F and
H) h. The lack of OX40L expression by activated lymph node T
cells is consistent with studies by others (23), and they
imply that OX40L expression on IELs is part of a specialized
communication network in the intestinal epithelium.
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synthesis, enhanced
cell-mediated cytotoxicity, and suppressed IL-10 production
The combined expression of OX40 and OX40L on activated IELs
suggests that an OX40-triggered signal is involved in the effector
response of CD3-stimulated IELs. To determine how OX40/OX40L expression
is functionally associated with IEL activation, three-color staining
was done for OX40 and CD8 expression in conjunction with intracellular
IFN- staining after overnight in vitro CD3-induced stimulation.
Similar to freshly isolated IELs (Fig. 1), IELs cultured for 16 h
with rIL-2 and rIL-15 but without CD3 stimulation remained negative for
intracellular IFN- staining (Fig. 6).
In contrast to unstimulated cells, approximately half of all
CD8+ IELs from 16-h CD3-stimulated cultures were
intracellular IFN-+. However, most important
was the finding that OX40 expression was exclusively associated with
the intracellular IFN-+ population of CD8 IELs
(Fig. 6), indicating that OX40 expression demarcates a population of
activated CD8+ IELs with newly acquired IFN-
synthesis.
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A,
OX40- cells retained lytic activity that was
very similar to that of freshly isolated cells; note that at an E:T
ratio of 25:1, both freshly isolated (Fig. 1) and
OX40- IELs from CD3-stimulated cultures (Fig. 7A) had 10–15% lytic activity in redirected assays. In
contrast, OX40+ IELs following CD3 stimulation
had consistently higher levels of lytic activity (67% in this
experiment at an E:T ratio of 25:1) (Fig. 7A).
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) from IEL
cultures after 24-h stimulation in wells containing immobilized
anti-CD3 and anti-OX40 mAbs or immobilized anti-CD3 and
control Ig mAbs. No appreciable difference was observed for IFN-
levels (Fig. 7B) or for IL-2 or IL-4 (data not shown) for
anti-OX40-costimulated vs control Ig cultures. These findings
indicate that even though OX40+ cells are the
principal source of IFN- (Fig. 6), direct costimulation via OX40
does not affect the level of IFN- produced by those cells. However,
of particular interest was the finding that anti-OX40 costimulation
of CD3-stimulated IELs significantly reduced the level of secreted
IL-10 (Fig. 7C). Note that because more cells are
OX40+ than are OX40L+ at
24 h (Fig. 3), the experimental system used in this study detects
the effects of OX40 ligation as soon as OX40 expression has occurred,
thus accounting for the difference between anti-OX40-stimulated and
control-stimulated cultures.
Finally, experiments were done to determine whether blockade of OX40
stimulation would alter IL-10 production. IELs were cultured with
immobilized anti-CD3 and control mAbs, with immobilized
anti-CD3 and anti-OX40 mAbs, or with immobilized anti-CD3
and soluble anti-OX40L mAbs. As shown in Fig. 7D,
blockade of OX40-OX40L binding using soluble anti-OX40L mAb (10
µg/ml) resulted in an increase of 22.4% in IL-10 production. These
findings were confirmed using a range of soluble anti-OX40L mAb in
CD3-stimulated cultures to block OX40-mediated activation; note the
dose-dependent effect of anti-OX40L blockade with maximal effect
(269.2% increase above anti-CD3 simulation alone) occurring at 8
µg/ml anti-OX40L mAb (Fig. 7E). As before,
anti-OX40 costimulation resulted in suppression of IL-10 synthesis
(Fig. 7E). These findings indicate that an OX40-triggered
signal during CD3 activation of murine IELs leads to suppressed
production of IL-10, and that the absence of OX40-OX40L interactions
results in markedly elevated levels of IL-10 synthesis by
IELs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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synthesis (Fig. 1). The induction of
intracellular IFN- activity upon CD3 stimulation is consistent with
prior observations for IELs (24) and now links that
functional response of IELs to a phenotypically defined effector
population. Because IFN- is known for its wide range of
immunobiological activities, indiscriminate IFN- production in the
absence of antigenic threat locally would not be needed and in fact
could be detrimental (25). However, rapid synthesis of
IFN- upon recognition and destruction of Ag-bearing target cells
would have a number of beneficial effects, including increases in MHC
expression (26), local antiviral activity
(27), and enhanced NK cell activity (28).
Moreover, in this system immune destruction of Ag-bearing tissues would
be achieved far more quickly than if activation were to take
place from a completely resting state, as occurs for most
extraintestinal peripheral T cells.
The presence of OX40L on CD8+ IELs after CD3
stimulation implies that the primary pathway of interactions for OX40
signaling to IELs occurs between CD8 T cells after TCR/CD3 stimulation
has taken place. Although regulated OX40L expression is a feature of
the DC response upon immune challenge (15), the potential
for this as a means of OX40 signaling in the intestinal epithelium is
unclear given that information regarding the distribution and numbers
of DCs in the intestinal epithelium is scant. In fact, best evidence
suggests that DCs are more sparsely located in the intestinal
epithelium than in the lamina propria or Peyer’s patches
(29). However, in that context, a process of intracellular
molecular transfer of OX40L onto T cells has recently been described,
involving the acquisition of OX40L on both CD4+
and CD8+ cells (30). Thus, it is
possible that OX40L expression on IELs is not due to de novo synthesis
by CD8+ IELs, but that it is acquired by the
active shedding of OX40L from a minor component of
OX40L+ cells within the total IEL population,
possibly a subset of the gut DCs alluded to above. Regardless, our
finding that both OX40 and OX40L are acquired on a significant
proportion of IELs within 24 h of CD3 stimulation, resulting in
greater efficiency in cytotoxic activity with concomitant IFN-
synthesis, defines a system of direct costimulatory activation between
resident CD8+ IELs.
A mechanistic model for the findings described in this work is shown in
Fig. 8. According to that model,
IEL activation after TCR engagement and CD3 signaling leads to rapid
up-regulation of OX40 and OX40L. Because under normal conditions this
would require an Ag-stimulated event, changes in OX40 and OX40L
expression would occur only on Ag-specific cells. CD3 signaling would
lead to rapid IFN- production by OX40+ cells
with a concomitant increase in cytotoxic activity. Additionally,
OX40-OX40L binding would suppress the overall production of IL-10 by
IELs, thereby further promoting cell-mediated immunity and enhancing
Th1 responses (31). Because IL-10 is known for its
counterregulatory effects on activities mediated by inflammatory
cytokines and chemokines (32, 33, 34, 35) and reduces resistance
to a wide range of intracellular pathogens (36, 37, 38),
suppressed levels of IL-10 would favor the generation of local immunity
during the early stages of local infection. However, sustained
OX40/OX40L expression on IELs would adversely promote local
inflammation and immunopathology by suppressing IL-10 synthesis
(39).
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(40). Yet a system of immunity such as this, while perhaps
logistically effective for dealing efficiently with the vast number of
Ags that confront the intestinal mucosa, has obvious potential
disadvantages in situations of Ag persistence or immune dysregulation
that lead to widespread inflammation. The use of OX40 as a marker for
discriminating IELs that have undergone recent activation should be
valuable for precisely identifying effector populations involved in
local immunity and for understanding changes in IEL populations
associated with inflammation and immunopathology.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. John R. Klein, Department of Basic Sciences, Dental Branch, University of Texas Health Science Center, Rm 4.133, 6516 M.D. Anderson Boulevard, Houston, TX 77030. E-mail address: John.R.Klein{at}uth.tmc.edu
3 Abbreviations used in this paper: IEL, intraepithelial lymphocyte; LCA, leukocyte common Ag; DC, dendritic cell; OX40L, OX40 ligand.
Received for publication March 29, 2001. Accepted for publication September 24, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/+ and /
+ T cells in murine intestinal epithelium. Eur. J. Immunol. 20:1623.[Medline]
or T cell receptor-bearing T cells from athymic nude mice are cytolytically active in vivo. J. Immunol. 147:1121.[Abstract]
+ intraepithelial lymphocytes. Science 243:1716.47/MAdCAM-1 and OX40/OX40 ligand in the colon and jejunum of patients with inflammatory bowel disease. Gut 45:856.+ intestinal intraepithelial lymphocytes. J. Immunol. 162:1896.+ intestinal intraepithelial lymphocytes. J. Immunol. 163:5843.+ and TCR+ T cells in an experimental model of colitis. Eur. J. Immunol. 27:17.[Medline]
mediated by the transactivator gene CIITA. Science 265:106. mediates the enhancement of spontaneous cytotoxicity in prolactin-activated natural killer cells. Immunology 98:386.[Medline]
- and interferon -induced genes by suppressing tyrosine phosphorylation of STAT1. Blood 93:1456. production by suppressing natural killer-cell stimulatory factor/IL-12 synthesis in accessory cells. J. Exp. Med. 178:1041.This article has been cited by other articles:
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  P. Soroosh, S. Ine, K. Sugamura, and N. Ishii OX40-OX40 Ligand Interaction through T Cell-T Cell Contact Contributes to CD4 T Cell Longevity J. Immunol., May 15, 2006; 176(10): 5975 - 5987. [Abstract] [Full Text] [PDF]
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W. Dawicki, E. M. Bertram, A. H. Sharpe, and T. H. Watts 4-1BB and OX40 Act Independently to Facilitate Robust CD8 and CD4 Recall Responses J. Immunol., November 15, 2004; 173(10): 5944 - 5951. [Abstract] [Full Text] [PDF]
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H.-C. Wang, D. Montufar-Solis, B.-B. Teng, and J. R. Klein Maximum Immunobioactivity of Murine Small Intestinal Intraepithelial Lymphocytes Resides in a Subpopulation of CD43+ T Cells J. Immunol., November 15, 2004; 173(10): 6294 - 6302. [Abstract] [Full Text] [PDF]
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P. Bansal-Pakala, B. S. Halteman, M. H.-Y. Cheng, and M. Croft Costimulation of CD8 T Cell Responses by OX40 J. Immunol., April 15, 2004; 172(8): 4821 - 4825. [Abstract] [Full Text] [PDF]
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A. Lugering, T. Kucharzik, D. Soler, D. Picarella, J. T. Hudson III, and I. R. Williams Lymphoid Precursors in Intestinal Cryptopatches Express CCR6 and Undergo Dysregulated Development in the Absence of CCR6 J. Immunol., September 1, 2003; 171(5): 2208 - 2215. [Abstract] [Full Text] [PDF]
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I. R. Humphreys, L. Edwards, G. Walzl, A. J. Rae, G. Dougan, S. Hill, and T. Hussell OX40 Ligation on Activated T Cells Enhances the Control of Cryptococcus neoformans and Reduces Pulmonary Eosinophilia J. Immunol., June 15, 2003; 170(12): 6125 - 6132. [Abstract] [Full Text] [PDF]
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H.-C. Wang, Q. Zhou, J. Dragoo, and J. R. Klein Most Murine CD8+ Intestinal Intraepithelial Lymphocytes Are Partially But Not Fully Activated T Cells J. Immunol., November 1, 2002; 169(9): 4717 - 4722. [Abstract] [Full Text] [PDF]
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