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*
Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia; and
Department of Medicine, University of Sydney, Sydney, Australia
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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4 integrin was
predominantly expressed on
ß1high/ß7-/low
cells, E integrin was primarily associated with
ß7high. The majority of activated/memory T
cells recruited during infection expressed high levels of
ß1 integrin and undetectable or low levels of
ß7 integrin. These T cells were capable of producing
IFN-
, a cytokine crucial for controlling M.
tuberculosis infection. Rapid expansion of
ß1high, ß7-, and
ß7high T cell populations in the lung upon
secondary mycobacterial infection indicates the participation of these
populations in the acquired immune response to the infection.
Furthermore, treatment of infected mice with mAb to 4 or
4ß7 integrin led to a reduction in
lymphocytes and increase in granulocytes in the pulmonary infiltrate.
These results reveal a crucial role for adhesion molecules in the
generation of an effective pulmonary immune response to M.
tuberculosis infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One group of HR, the integrins, are heterodimic proteins consisting of
noncovalently associated - and ß-chains important in regulating
lymphocyte homing. They have been divided into subfamilies according to
their ß-chains (8), with the ß1,
ß2, and ß7 integrin
subfamilies important in the leukocyte-endothelial interaction
(2). The -chain of the heterodimer determines the
specificity of the integrin.
4ß1 (VLA-4) integrin
is mainly expressed on leukocytes involved in binding to VCAM-1 and
fibronectin (9). Importantly, the VLA-4:VCAM-1 interaction
facilitates recruitment of lymphocytes to inflamed extraintestinal
mucosal tissues (4, 10), exemplified by anti-VLA-4 and
anti-VCAM-1 mAb treatment preventing the migration of lymphocytes
into sites of inflammation in vivo (11, 12, 13).
Interestingly, 4 integrin can also associate
with ß7 integrin to form the
4ß7 heterodimer. Like
4ß1,
4ß7 integrin is able
to bind to both VCAM-1 and fibronectin (14, 15), but a
major ligand for 4ß7
is the mucosal addressin cell adhesion molecule-1 (MadCAM-1). Because
MadCAM-1 is only expressed on high endothelial venules of Peyer’s
patches and mesenteric lymph nodes (16, 17), this
interaction highlights the importance of the
4ß7 heterodimer in the
differential recirculation of lymphocytes to mucosal surfaces. Another
member of the ß7 integrin subfamily is
Eß7.
Eß7 integrin retains
lymphocytes within the epithelium via binding to E-cadherin on
epithelial cells (18, 19), rather than acting as a homing
molecule for the mucosa (20, 21, 22).
Tuberculosis, primarily a lung disease, is the world’s leading cause
of death from a single infectious agent, and represents 25% of all
preventable deaths (23). The major protective immune
response against M. tuberculosis infection is the activation
of Ag-specific CD4+ and
CD8+ T cells. The secretion of IFN- and other
cytokines by these T cells leads to the containment of the bacillus by
activated macrophages (24, 25). The mechanisms that govern
the recruitment of circulating lymphocytes into the M.
tuberculosis-infected lungs are not fully understood, particularly
with regard to the contribution of the different integrin families.
To explore the mechanisms that control lymphocyte migration into the lung in normal and pathological situations, we used an aerosol model of M. tuberculosis infection in the mouse to investigate the changes in the expression of addressins on endothelium and ß integrins on T cells in the lung during infection. In this study, we show that an up-regulation of endothelial expression of VCAM-1 and differential expansion of ß integrin-expressing T cells are important in the lymphocyte trafficking to the lungs following aerosol mycobacterial infection. These adhesion molecules are crucial to coordinate an appropriate pulmonary inflammatory response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 female mice were supplied by Animal Resources Centre (Perth, WA, Australia), and were maintained in specific pathogen-free conditions at the Centenary Institute animal facility until infection with M. tuberculosis, when they were transferred to and maintained in a level 3 physical containment facility. Mice were used between 6 and 8 wk of age.
Bacteria and aerosol infection
M. tuberculosis H37Rv (ATCC 27294) was grown in
Proskauer and Beck liquid medium (Difco, Detroit, MI), for 14 days at
37°C. Mycobacterium bovis, bacille Calmette-Guerin (BCG;
CSL strain), was prepared in supplemented Middlebrook 7H9 broth (Difco)
for 14 days at 37°C. The bacteria were washed, and enumerated on
supplemented Middlebrook 7H11 Agar (Difco). Mice were exposed to
M. tuberculosis H37Rv in a Middlebrook airborne infection
apparatus (Glas-Col, Terre Haute, IN) at a predetermined infective
dose. Each mouse received 
102 viable bacilli
per lung, as determined by culture of lung homogenates 24 h after
infection. Exposure to aerosol BCG occurred in an infection apparatus
that delivered an infectious dose of 103 viable
BCG organisms to the lung. This resulted in comparable kinetics in the
bacterial load and T cell responses in the lung to that
following aerosol M. tuberculosis infection (C.
Feng and U. Palendira, unpublished data). For the secondary
infection experiments, 8 wk after primary infection with aerosol
BCG, groups of mice were treated with Isoniazid (Sigma, St.
Louis, MO) (2% in drinking water) for 4 wk to reduce bacterial load.
The mean (±SEM) CFU for three mice after antibiotic treatment and
before secondary challenge was 227 (±32.15) per lung. Two weeks after
the completion of drug treatment, half of these infected and treated
mice were exposed to a secondary aerosol infection with the same dose
of the BCG as primary infection. The remaining mice served as controls
to illustrate the level of the integrin expression following treated
primary infection.
In vivo Ab treatment
Protein G column-purified rat mAb to 4
(clone PS/2), 4ß7
(clone DATK32), and an irrelevant control rat mAb (clone GL113) were
used in in vivo mAb treatment experiments. Mice were infected with
aerosol M. tuberculosis and were injected (i.p.)
with 500 µg of mAb on day 14, and then on alternate days until day
28. Control mice received GL113 or were left untreated. This protocol
was chosen because there was no significant increase in the numbers of
lymphocytes in the lungs before day 14 postinfection with aerosol
M. tuberculosis (see Fig. 3
B) (26).
The concentration of rat IgG (measured by ELISA) in the sera of mice
was 4–18 µg/ml at 24 h, and 2–5 µg/ml at 48 h after mAb
treatment. At the end of the experiments, one lung was homogenized and
serially diluted for determination of CFU of M.
tuberculosis. The other lung was used for histological and FACS
analysis.
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Animals were sacrificed by carbon dioxide narcosis at defined time points after aerosol infection. The lungs were gently perfused with 20 U/ml heparin (Fisons Pharmaceuticals, NSW, Australia) in PBS. Lung tissue was minced and then incubated for 90 min at 37°C with shaking in RPMI (1 lung/5 ml) supplemented with 50 U/ml collagenase I, type 4197 (Worthington, Freehold, NJ), and 13 µg/ml DNase I (Boehringer Mannheim, Mannheim, Germany). After incubation, a single cell suspension was prepared by removing large aggregates and debris by passage through a 100-µm mesh.
Abs for flow cytometry
The following mAbs were used for flow cytometry: anti-CD44
FITC (clone IM7; PharMingen, San Diego, CA), anti-CD49d
(4 integrin) FITC (clone R1-2; PharMingen),
anti-CD103 (E integrin) FITC (clone 2E7;
PharMingen), anti-ß7 integrin-PE (clone
M293; PharMingen), and biotin-conjugated anti-CD29
(ß1 integrin) (clone Ha2/5; PharMingen).
Anti-CD4 Tri-color (clone CT-CD4), anti-CD8 Tri-color (clone
CT-CD8a), and isotype control Abs were purchased from Caltag (San
Francisco, CA). Streptavidin conjugated with PE (Caltag) was used as a
secondary reagent for biotin-labeled Abs.
Cell surface staining and flow cytometry
The detailed procedures for the surface staining and FACS analysis of lung cells have been previously described (27). The staining of samples with isotype control Ab was used as reference to determine positive and negative populations.
Intracellular IFN- staining
Single cell suspensions of lung cells were incubated in a
six-well plate at 37°C for 1 h to remove adherent cells.
Nonadherent cells (106/ml) were then stimulated
with plate-bound anti-CD3 mAb (PharMingen) (10 µg/ml) for 16
h in complete RPMI (RPMI supplemented with 10% FCS, 2 mM
L-glutamine, 10 mM HEPES, 0.5 µM 2-ME, 100 U/ml
penicillin, and 100 µg/ml streptomycin). Brefeldin A (Sigma) (10
µg/ml) was added to the cultures for the final 4 h. Cells were
washed and surface stained with rat anti-mouse CD4 or CD8 mAb
(Caltag). The cells were fixed in 4% paraformaldehyde for 20 min at
room temperature, washed in permeabilization buffer (0.1% saponin in
FACS buffer), then stained with anti-IFN- FITC (clone AN18) in
permeabilization buffer at 4°C for 30 min. Cells were then washed in
permeabilization buffer, resuspended in FACS buffer, and analyzed on a
FACScan flow cytometer (as described).
Immunohistology
Air-dried frozen sections (4–6 µm) were double stained by indirect immunofluorescence with rabbit anti-cytokeratin polyclonal Ab (Dako, Carpenteria, CA), to reveal epithelial cells, and either rat anti-mouse mAb specific for E-cadherin (clone ECCD-2; Zymed, South San Francisco, CA), ICAM-1 (clone 3E2; PharMingen), MadCAM-1 (clone MECA-367; PharMingen), or VCAM-1 (clone 429; PharMingen). This was followed by staining with either goat anti-rat or goat anti-hamster Ig conjugated to FITC (Caltag) and tetramethylrhodamine isothiocyanate-conjugated goat anti-rabbit IgG (Southern Biotechnology Associates, Birmingham, AL). To increase the sensitivity of staining, a single stain, three-step procedure for detection of MadCAM-1 was developed. Tissue sections were incubated with the mAb to MadCAM-1, followed by a rabbit anti-rat IgG (Dako). A FITC-conjugated goat anti-rabbit IgG (Caltag) was then used to visualize the staining. Sections were stained with Abs, 20 min in a moist chamber at room temperature, and after each step the sections were washed three times for 5 min each with PBS. Sections were examined on a Leitz DMR BE fluorescence microscope (Leica, St. Gallen, Switzerland).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recruitment of lymphocytes to nonlymphoid organs, such as the
lung, is mediated by the interaction between addressins on endothelium
and HR on lymphocytes. We compared the expression of ICAM-1, VCAM-1,
MadCAM-1, and E-cadherin in normal lungs and lungs at 2, 4, 8, and 12
wk following aerosol M. tuberculosis infection. The
expression of VCAM-1 was observed on the endothelium only in infected
lungs (Fig. 1). The up-regulated VCAM-1
expression was present from week 4 and maintained at least to week 12
postinfection. By contrast, there was little change in the expression
of ICAM-1 and E-cadherin (data not shown). MadCAM-1 expression was not
detected in either normal or infected lung by either two- or three-step
staining techniques, both of which revealed positive staining for
MadCAM-1 expression in Peyer’s patches (data not shown).
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Because VCAM-1 expression was up-regulated in the lung infected
with M. tuberculosis and both
4ß1 or
4ß7 integrins may act
as a counter-receptor for this addressin, we investigated the
expression of ß1 and ß7
integrin on pulmonary T cells. In uninfected lung, while the majority
of lung T cells expressed low levels of ß1
integrin (Fig. 2A, upper
panel), the expression of ß7 integrin was
heterogeneous (Fig. 2B, upper panel). M.
tuberculosis infection resulted in a shift in
ß1 integrin expression from predominantly
ß1low to an accumulation of
ß1high T cells (Fig. 2A, lower panel). In contrast, changes in
ß7 integrin-expressing T cells displayed a
reciprocal pattern, with a marked increase of T cells with undetectable
or low levels of ß7 integrin (Fig. 2B, lower panel). Interestingly, a small
population of CD4+ and CD8+
T cells expressing a higher level of ß7
integrin also emerged during infection (Fig. 2B, lower
panel). To relate the expression of ß1
integrin to that of ß7 integrin, the
coexpression of these two ß-chains on CD4+ and
CD8+ T cells was analyzed. Fig. 2C
shows that ß1high T cells
tended to express low or undetectable levels of
ß7 integrin, and mycobacterial infection in
lung resulted in an expansion of
ß1high/ß7-/low
CD4+ and CD8+ T cells (Fig. 2C).
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4ß1high T
cells in the lungs during M. tuberculosis infection
As the -chain of integrin heterodimers confers the specificity
of binding, the expression of
4ß1high
(VLA-4) was analyzed. M. tuberculosis infection
led to an increase in numbers of both CD4+ and
CD8+ T cells expressing
4 integrin. This increase was associated with
the increased expression of ß1 integrin (Fig. 3
A). Kinetic studies of the
emergence of this population revealed that the expansion of
4ß1high
T cells was apparent 4 wk after infection, and peaked at 8 wk with
>100-fold increase for both CD4+ and
CD8+
4ß1high
T cells (Fig. 3B).
Development of 4ß7 and
Eß7 T cell populations in lung during
M. tuberculosis infection
As for ß1, ß7
integrin can associate with 4 integrin
(CD49d), but it may also pair with E integrin
(CD103). Recent studies have indicated that
4ß7 and
Eß7 integrins are
important in the homing and retention of mucosal lymphocytes to mucosal
surfaces (20, 21). We therefore compared the distribution
of 4ß7 and
Eß7 integrins on lung
T cells in normal and infected lung by costaining of
ß7 with either 4 or
E integrin. Only a small percentage of T cells
expressed 4ß7 integrin
in normal lung (Fig. 4A,
upper panel). M. tuberculosis infection, however,
led to an increase in 4 integrin-expressing T
cells (Fig. 4A, lower panel); the majority of
these T cells expressed low or undetectable levels of
ß7 integrin (Fig. 4A, lower
panel). Intriguingly, the expression patterns of
E integrin on CD4+ and
CD8+ T cells were different. In uninfected lung,
E was expressed on only a minority of
CD4+ T cells, whereas approximately one-half of
CD8+ T cells were E
positive (Fig. 4B, upper panel). After infection,
there was a small, but definite, increase in the
E CD4+ T cells (from 2%
to 10%) (Fig. 4B, lower panel). The changes of
E CD8+ T cells were more
complex. There was a significant decrease in the proportion of
E CD8+ T cells (from
53% to 23%). However, as with the CD4+ T cells,
a minor population of CD8+ T cells expressing
very high levels of
Eß7 emerged in the
infected lungs (from 1% to 6%). Taken together, it appears that
during infection, 4 integrin was primarily
expressed on ß7-/low T cells (Fig. 4A, lower panel), and
Eß7 T cells tended to
express high or very high levels of ß7 integrin
(Fig. 4B, lower panel).
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A preferential accumulation of some subsets of
ß1 and ß7
integrin-expressing T cells in infected lung suggested that these T
cells were of special relevance to the host immune response. We
therefore examined the expression of ß integrins on activated/memory
T cells by costaining for CD44 with either ß1
or ß7 integrin. In agreement with our previous
report (26), M. tuberculosis infection resulted
in a significant enrichment of CD44high T cells
(Fig. 5A), and these T cells
expressed high levels of ß1 integrin (Fig. 5A). However, a more complex pattern was displayed with
regard to the expression of ß7 integrin.
Although subpopulations of
ß7-,
ß7low, and
ß7high activated/memory T
cells were present, ß7-/low T
cells constituted the dominant activated/memory T cell population
(Fig. 5B).
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is predominantly produced by
ß1high/ß7-/low T
cells in the infected lungs
Because IFN- is an essential component of protective immunity
against M. tuberculosis infection (28, 29), we
examined the phenotypes of IFN--producing T cells by costaining for
the ß integrins and IFN-. As expected, the number of
IFN--producing T cells was greater in infected than that in normal
lungs. The majority of the IFN--producing CD4+
and CD8+ T cells expressed a high level of
ß1 integrin (Fig. 6A). With regard to
ß7 integrin expression, the major
IFN--producing T cell population expressed low or undetectable
levels of ß7 integrin, although
IFN--producing ß7high, most
likely in association with E integrin (Fig. 4B), CD8+ T cells were also evident
(Fig. 6B).
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Acquired immunity to mycobacterial infection is dependent on the
rapid expansion of memory T cells generated from primary infection with
CD4+ T cells as the predominant protective cells
(24, 25). We therefore compared the expression of
ß1 and ß7 integrin on
CD4+ T cells during primary and secondary
infection. After primary aerosol BCG infection was established,
infected mice were treated with antibiotics to reduce bacterial load
before secondary aerosol challenge. The percentage of
ß1high
CD4+ T cells in the antibiotic-treated mice (Fig. 7, group 2) was similar to that in mice 2
wk after single aerosol infection (Fig. 7, group 3) and only slightly
higher than in control uninfected mice (Fig. 7, group 1). Reexposure of
the primary infected, antibiotic-treated mice to secondary infection
(Fig. 7, group 4) resulted in a rapid and significant expansion of
ß1high
CD4+ T cells (2.7-fold increase compared with
control group) by 2 wk postinfection (Fig. 7A). This
increased percentage of ß1high
CD4+ T cells corresponded with a similar increase
in the percentage of ß7-
CD4+ T cells (2.5-fold increase) (Fig. 7B). A significant increase in
ß7high
CD4+ T cells was also observed in the lungs after
reexposure (3.2-fold increase) (Fig. 7C).
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4 or 4ß7 integrin leads
to a detrimental pulmonary inflammatory response
To investigate further the contribution of
4 and
4ß7 integrins to the
cell-mediated immune response to M. tuberculosis in the
lungs, aerosol-infected mice were treated with mAb to
4 or
4ß7 integrin from day
14 postinfection. Experiments were terminated on day 28, as both
4 and
4ß7 integrin
mAb-treated mice were hunched and wasting. Table I shows that treatment with mAb to
4 or
4ß7 integrin resulted
in a significant reduction in the numbers of lymphocytes, and an
increase in granulocyte numbers in the lungs. Histological
examination of the infected lungs showed that granulomas in untreated
infected (Fig. 8A) or control
mAb-treated mice (Fig. 8B) were well defined and were
comprised largely of lymphocytes and macrophages (Fig. 8, E
and F). In contrast, treatment with integrin-specific mAb
led to the formation of enlarged and disorganized lesions (Fig. 8, C and D), containing predominantly neutrophils
and necrotic debris (Fig. 8, G and H).
Interestingly, the treatment of mice with mAb to
4 and
4ß7 integrin did not
significantly alter the bacterial load in the lungs (Table I), despite
the clinical deterioration of the mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The current study demonstrates that the interaction of VCAM-1 and
4ß1 integrin has a
role in the recruitment of activated T cells to the lung following
aerosol infection. In the lungs of uninfected mice, VCAM-1 was not
detectable on pulmonary endothelium (Fig. 1), and
4ß1 integrin was
expressed at low levels on resident T cells (Fig. 3). After aerosol
M. tuberculosis infection, the expression of VCAM-1 on
endothelial cells occurred from week 4 and still persisted at week 12
in the infected lungs (Fig. 1). This up-regulated expression of VCAM-1
correlated with the accumulation of activated/memory T cells expressed
high levels of 4ß1
integrin (Fig. 3). The peak of the influx of
4ß1high
CD4+ and CD8+ T cells
coincided with the maximum cellular infiltrate in the lungs, and these
cells were the major IFN--producing cells (Fig. 6A).
Furthermore, the accelerated expansion of
ß1high/ß7-
CD4+ T cells in the lung following secondary
infection (Fig. 7, A and B) was associated with
the rapid control of infection, and a reduced bacterial load than
during primary infection (U. Palendira, manuscript in preparation).
Taken together, these findings suggest that the
4ß1:VCAM-1 interaction
leads to the recruitment of activated T cells into the inflamed lungs
and contributes to the control of mycobacterial infection in the lung.
Analysis of addressins and integrin expression during
Chlamydia infection also demonstrated up-regulation of
VCAM-1 expression and accumulation of
ß1high/ß7-/low-activated
T cells in the genital mucosa (32), Thus, these findings
underline the importance of the
4ß1:VCAM-1 interaction
in the homing of activated T cells to extraintestinal mucosa.
Interestingly, other studies of genital Chlamydia infection
have revealed up-regulation of MadCAM-1 and recruitment of
4ß7
integrin-expressing CD4+ T cells into genital
tract (38), demonstrating that a complex pattern of
addressin and integrin interaction may occur during inflammatory
response to infection in extraintestinal mucosal tissues.
Because VCAM-1 can bind to both
4ß1 and
4ß7 heterodimers, we
investigated the role of these two integrins in the cellular response
to M. tuberculosis infection. Treatment of infected mice in
vivo with mAb to 4 integrin, which binds to
both 4ß1 and
4ß7 integrins, led to
a significant reduction in the number of lymphocytes and to an influx
of neutrophils into infected lungs (Table I). It has been shown that
anti-4 mAb treatment does not block
neutrophil recruitment (39). This dysregulation of the
inflammatory response resulted in development of
granulocyte-predominant, disorganized infiltrates that progressed to
necrosis (Fig. 8). Similar necrotic lesions have been reported in mice
lacking the critical protective cytokines, IFN- and TNF (27, 28). This suggests that the influx of neutrophils is an attempt
to compensate for ineffective lymphocyte responses. Despite the altered
inflammatory responses and the clinical deterioration in mice, there
was no significant difference in the bacterial load in the lungs
between treated and untreated mice. This may be due to the relatively
short time course of the mAb treatment compared with slow rate of
mycobacterial growth, or to other factors. Treatment with mAb to
4ß7 integrin also
reduced the number of lymphocytes in the lungs by 40%. VCAM-1 may act
as an alternative ligand for
4ß7 integrin
(14, 15) with low levels of VCAM-1 preferentially
recruiting
4ß1highß7-
cells, and high expression of VCAM-1 favoring
4ß7 integrin binding
(40). Therefore, the observed recruitment of
4ß7-expressing
lymphocytes to the inflamed lungs could have occurred in the absence of
detectable expression of MadCAM-1, presumably through the interaction
with VCAM-1.
The expression of Eß7
integrin on pulmonary lymphocytes is less well understood. M.
tuberculosis infection appeared to have differential effects on
the expression of Eß7
integrin on CD4+ and CD8+ T
cells. In contrast to the CD4+ T cells, the
proportion of
E+ß7high
CD8+ T cells decreased significantly in infected
lung owing to the expansion of
4ß1-expressing
CD8+ T cells. This observation supports the
hypothesis that expression of
Eß7 on
CD8+ T cells in lung is not related to
inflammatory stimuli, but is due to constitutive factors in the
pulmonary microenvironment (31, 41). Intriguingly, we also
observed the emergence of a small population of
CD8+ T cells with very high levels of
ß7 integrin associated with
E integrin in infected lungs (Fig. 4B). These ß7high
CD4+ and CD8+ T cells were
CD44high (Fig. 5B), and the
ß7high
CD8+ T cells were capable of producing
IFN- (Fig. 6B), suggesting that these were
activated/memory T cells. The expression of high levels of
Eß7 integrin may favor
the retention of these cells on epithelial surface via interaction with
E-cadherin. Taken together, the activation and expansion of these
Eß7high
T cells in the infected lungs indicate that along with
4ß1high
T cells, this small population may also contribute to the host
pulmonary responses through the production of IFN-. The precise role
of Eß7
integrin-expressing T cells in protective immunity against
mycobacterial infection in the lung needs to be further
investigated.
In conclusion, up-regulated expression of VCAM-1 and the increased
numbers of
4ß1high
T cells during pulmonary tuberculosis suggest that the
4ß1:VCAM-1 interaction
contributes to the recruitment of activated T cells to the infected
lung. There are also significant increases in
ß7high integrin-expressing T
cells that participate in the prompt memory response to the reexposure
to mycobacterial infection. The complex pattern of integrin expression
and the impaired inflammatory response on treatment with mAb to
4 and
4ß7 integrins indicate
that multiple adhesion molecules appear to contribute to the pulmonary
inflammatory response to aerosol M. tuberculosis.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. W. J. Britton, Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No 6, Newtown, NSW, 2042 Australia.
3 Current address: CSIRO, Division of Animal Health, Private Bag 24, Geelong, Victoria, 3220 Australia.
4 Abbreviations used in this paper: HR, homing receptor; BCG, bacille Calmette-Guerin; MadCAM-1, mucosal addressin cell adhesion molecule-1; VLA, very late activation.
Received for publication May 3, 1999. Accepted for publication February 24, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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M. Santosuosso, S. McCormick, E. Roediger, X. Zhang, A. Zganiacz, B. D. Lichty, and Z. Xing Mucosal Luminal Manipulation of T Cell Geography Switches on Protective Efficacy by Otherwise Ineffective Parenteral Genetic Immunization J. Immunol., February 15, 2007; 178(4): 2387 - 2395. [Abstract] [Full Text] [PDF]
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T. M. Wozniak, A. A. Ryan, and W. J. Britton Interleukin-23 Restores Immunity to Mycobacterium tuberculosis Infection in IL-12p40-Deficient Mice and Is Not Required for the Development of IL-17-Secreting T Cell Responses J. Immunol., December 15, 2006; 177(12): 8684 - 8692. [Abstract] [Full Text] [PDF]
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S. Ghosh, A. A. Chackerian, C. M. Parker, C. M. Ballantyne, and S. M. Behar The LFA-1 adhesion molecule is required for protective immunity during pulmonary Mycobacterium tuberculosis infection. J. Immunol., April 15, 2006; 176(8): 4914 - 4922. [Abstract] [Full Text] [PDF]
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M. Santosuosso, X. Zhang, S. McCormick, J. Wang, M. Hitt, and Z. Xing Mechanisms of Mucosal and Parenteral Tuberculosis Vaccinations: Adenoviral-Based Mucosal Immunization Preferentially Elicits Sustained Accumulation of Immune Protective CD4 and CD8 T Cells within the Airway Lumen J. Immunol., June 15, 2005; 174(12): 7986 - 7994. [Abstract] [Full Text] [PDF]
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C. G. Feng, D. Jankovic, M. Kullberg, A. Cheever, C. A. Scanga, S. Hieny, P. Caspar, G. S. Yap, and A. Sher Maintenance of Pulmonary Th1 Effector Function in Chronic Tuberculosis Requires Persistent IL-12 Production J. Immunol., April 1, 2005; 174(7): 4185 - 4192. [Abstract] [Full Text] [PDF]
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 R. K. Pai, M. E. Pennini, A. A. R. Tobian, D. H. Canaday, W. H. Boom, and C. V. Harding Prolonged Toll-Like Receptor Signaling by Mycobacterium tuberculosis and Its 19-Kilodalton Lipoprotein Inhibits Gamma Interferon-Induced Regulation of Selected Genes in Macrophages Infect. Immun., November 1, 2004; 72(11): 6603 - 6614. [Abstract] [Full Text] [PDF]
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C. W. Lawrence and T. J. Braciale Activation, Differentiation, and Migration of Naive Virus-Specific CD8+ T Cells during Pulmonary Influenza Virus Infection J. Immunol., July 15, 2004; 173(2): 1209 - 1218. [Abstract] [Full Text] [PDF]
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M. H. Qureshi, J. Cook-Mills, D. E. Doherty, and B. A. Garvy TNF-{alpha}-Dependent ICAM-1- and VCAM-1-Mediated Inflammatory Responses Are Delayed in Neonatal Mice Infected with Pneumocystis carinii J. Immunol., November 1, 2003; 171(9): 4700 - 4707. [Abstract] [Full Text] [PDF]
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B. Xu, N. Wagner, L. N. Pham, V. Magno, Z. Shan, E. C. Butcher, and S. A. Michie Lymphocyte Homing to Bronchus-associated Lymphoid Tissue (BALT) Is Mediated by L-selectin/PNAd, {alpha}4{beta}1 Integrin/VCAM-1, and LFA-1 Adhesion Pathways J. Exp. Med., May 19, 2003; 197(10): 1255 - 1267. [Abstract] [Full Text] [PDF]
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 M J Leckie, G R Jenkins, J Khan, S J Smith, C Walker, P J Barnes, and T T Hansel Sputum T lymphocytes in asthma, COPD and healthy subjects have the phenotype of activated intraepithelial T cells (CD69+ CD103+) Thorax, January 1, 2003; 58(1): 23 - 29. [Abstract] [Full Text] [PDF]
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T. M. Doherty, A. W. Olsen, L. van Pinxteren, and P. Andersen Oral Vaccination with Subunit Vaccines Protects Animals against Aerosol Infection with Mycobacterium tuberculosis Infect. Immun., June 1, 2002; 70(6): 3111 - 3121. [Abstract] [Full Text] [PDF]
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D. R. Roach, A. G. D. Bean, C. Demangel, M. P. France, H. Briscoe, and W. J. Britton TNF Regulates Chemokine Induction Essential for Cell Recruitment, Granuloma Formation, and Clearance of Mycobacterial Infection J. Immunol., May 1, 2002; 168(9): 4620 - 4627. [Abstract] [Full Text] [PDF]
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U. Palendira, A. G. D. Bean, C. G. Feng, and W. J. Britton Lymphocyte Recruitment and Protective Efficacy against Pulmonary Mycobacterial Infection Are Independent of the Route of Prior Mycobacterium bovis BCG Immunization Infect. Immun., March 1, 2002; 70(3): 1410 - 1416. [Abstract] [Full Text] [PDF]
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 L. Stevceva, B. Kelsall, J. Nacsa, M. Moniuszko, Z. Hel, E. Tryniszewska, and G. Franchini Cervicovaginal Lamina Propria Lymphocytes: Phenotypic Characterization and Their Importance in Cytotoxic T-Lymphocyte Responses to Simian Immunodeficiency Virus SIVmac251 J. Virol., January 1, 2002; 76(1): 9 - 18. [Abstract] [Full Text] [PDF]
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D. J. Topham, M. R. Castrucci, F. S. Wingo, G. T. Belz, and P. C. Doherty The Role of Antigen in the Localization of Naive, Acutely Activated, and Memory CD8+ T Cells to the Lung During Influenza Pneumonia J. Immunol., December 15, 2001; 167(12): 6983 - 6990. [Abstract] [Full Text] [PDF]
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 A. G. Jarnicki, T. Tsuji, and W. R. Thomas Inhibition of mucosal and systemic Th2-type immune responses by intranasal peptides containing a dominant T cell epitope of the allergen Der p 1 Int. Immunol., October 1, 2001; 13(10): 1223 - 1231. [Abstract] [Full Text] [PDF]
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D. Finke, F. Baribaud, H. Diggelmann, and H. Acha-Orbea Extrafollicular Plasmablast B Cells Play a Key Role in Carrying Retroviral Infection to Peripheral Organs J. Immunol., May 15, 2001; 166(10): 6266 - 6275. [Abstract] [Full Text] [PDF]
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J. Turner, M. Gonzalez-Juarrero, B. M. Saunders, J. V. Brooks, P. Marietta, D. L. Ellis, A. A. Frank, A. M. Cooper, and I. M. Orme Immunological Basis for Reactivation of Tuberculosis in Mice Infect. Immun., May 1, 2001; 69(5): 3264 - 3270. [Abstract] [Full Text] [PDF]
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J. A. Burns, T. B. Issekutz, H. Yagita, and A. C. Issekutz The {{alpha}}4{{beta}}1 (Very Late Antigen (VLA)-4, CD49d/CD29) and {{alpha}}5{{beta}}1 (VLA-5, CD49e/CD29) Integrins Mediate {{beta}}2 (CD11/CD18) Integrin-Independent Neutrophil Recruitment to Endotoxin-Induced Lung Inflammation J. Immunol., April 1, 2001; 166(7): 4644 - 4649. [Abstract] [Full Text] [PDF]
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M. Gonzalez-Juarrero, O. C. Turner, J. Turner, P. Marietta, J. V. Brooks, and I. M. Orme Temporal and Spatial Arrangement of Lymphocytes within Lung Granulomas Induced by Aerosol Infection with Mycobacterium tuberculosis Infect. Immun., March 1, 2001; 69(3): 1722 - 1728. [Abstract] [Full Text] [PDF]
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