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Receptor 2 in the Regulation of Airway Hyperresponsiveness by 
T Cells1
Departments of
* Pediatrics and
Immunology, Program in Cell Biology, National Jewish Medical and Research Center, Denver, CO 80206
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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negatively regulates
airway responsiveness through the activation of 
T cells. The
biological activities of TNF- are mediated by two structurally
related but functionally distinct receptors, p55 (TNFR1) and p75
(TNFR2), which are independently expressed on the cell surface.
However, the relative importance of either TNFR in airway
hyperresponsiveness (AHR) is unknown. To investigate the importance of
these TNFRs in the development of allergen-induced AHR, p55-deficient
and p75-deficient mice were sensitized to OVA by i.p. injection and
subsequently challenged with OVA via the airways; airway responsiveness
to inhaled methacholine was monitored. p75-deficient mice developed AHR
to a similar degree as control mice. In contrast, p55-deficient mice,
which were sensitized and challenged with OVA, failed to develop AHR.
In p55-deficient mice, both the numbers of eosinophils and levels of
IL-5 in bronchoalveolar lavage fluid were significantly lower than in
sensitized/challenged control mice (p < 0.05).
However, depletion of T cells resulted in significant increases
in AHR in the p55-deficient mice, whereas no significant effect of
T cell depletion was evident in the p75-deficient mice. These
data indicate that, in the absence of TNFR1 (p55), where TNF- uses
the p75 pathway exclusively, the development of AHR is regulated by
T cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is identified as an important mediator of early T
cell activation and of differential proliferative responses. The
biological activities of TNF- are mediated by two structurally
related but functionally distinct receptors, p55 (TNFR1) and p75
(TNFR2), which are independently expressed on the cell surface
(1, 2). Some studies indicate that the p55 receptor is the
primary signaling receptor on most cell types through which the
majority of inflammatory responses classically attributed to TNF-
are mediated. In contrast, TNF--induced thymocyte proliferation,
TNF--mediated skin necrosis, and apoptosis of activated, mature T
lymphocytes are mediated through the p75 receptor (3, 4, 5).
Specifically, animals lacking the p55 receptor do not develop
inflammatory reactions in response to TNF-, whereas animals lacking
p75 receptor remain responsive (6, 7). Human airway tissue
expresses both types of TNFRs (8), but their functional
importance is only just emerging. Activation through p55 results in
proliferation of human tracheal smooth muscle cells; in contrast,
specific stimulation of the p75 receptor with recombinant TNF- did
not induce these effects (9).
In a recent study we found that T cells down-regulate airway
hyperresponsiveness
(AHR)3 in a mouse
model of airway inflammation and hyperresponsiveness (10).
We also reported that TNF- negatively regulates airway
responsiveness through T cells (11). In an earlier
study we found that T cells respond more strongly to TNF-
than do 
T cells (12). The stronger response of
T cells to TNF- was correlated with higher levels of the
inducible expression of the p75 receptor (12). However,
the relative importance of either of the TNF- receptors in AHR and
airway inflammation, characterized by an influx of activated
eosinophils and T lymphocytes (13, 14, 15), is to a large
extent unknown.
To clarify the significance of the two TNFRs in the development of
allergen-induced AHR, TNFR p55-deficient and p75-deficient mice were
sensitized to OVA by i.p. injection and subsequently challenged with
OVA via the airways. We monitored airway responses to inhaled
methacholine (MCh) and inflammatory cell infiltration in the airways
and also investigated the consequences of depletion of T cells
on these responses. The results revealed distinct functions of these
two receptors on the development of these responses as well as their
influence on T cell function.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6 mice from 8 to 10 wk of age were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice genetically deficient for TNFR p55 and TNFR p75 (16) (back-crossed onto the C57BL/6 genetic background) from 8 to 10 wk of age were a gift from Dr. D. Lynch (Immunex, Seattle, WA). The mice were maintained on OVA-free diets. All experimental animals used in this study were under a protocol approved by the Institutional Animal Care and Use Committee of the National Jewish Medical and Research Center.
Experimental protocol
Each strain of mouse was grouped based on the following treatments (four mice per group per experiment): 1) airway challenge (three times) with OVA nebulization alone (N group); and 2) i.p. sensitization (two times) with OVA and OVA airway challenge (three times) (IPN group). Mice were sensitized by i.p. injection of 20 µg of OVA (grade V; Sigma-Aldrich, St. Louis, MO) emulsified in 2.25 mg alum (AlumImuject; Pierce, Rockford, IL) in a total volume of 100 µl on days 0 and 14. Mice were challenged via the airways to OVA (1% in saline) for 20 min on days 28, 29, and 30 by ultrasonic nebulization (De Vilbiss; particle size 1–5 µm). Lung resistance (RL) and dynamic compliance (Cdyn) were assessed 48 h after the last allergen challenge, and the mice were sacrificed to obtain tissues and cells for further assays.
Determination of airway responsiveness to inhaled MCh
RL and Cdyn were determined as a change in airway function after aerosolized MCh challenge. Anesthetized, tracheostomized mice were mechanically ventilated and lung function was assessed as described (17). Aerosolized MCh was administered for 10 breaths at a rate of 60 breaths/min, tidal volume of 500 µl by the ventilator (model 683; Harvard Apparatus, South Natick, MA) in increasing concentrations (6.25, 12.5, 25, 50, and 100 mg/ml). After each MCh challenge, the data were continuously collected for 1–5 min and maximum values of RL and minimum values of Cdyn were taken to express changes in these functional parameters.
Determination of cell numbers and cytokine levels in bronchoalveolar lavage fluid (BALF)
Immediately after assessment of RL and Cdyn, lungs were lavaged via the tracheal tube with HBSS (1 x 1 ml at 37°C). The volume of collected BALF was measured in each sample and the number of bronchoalveolar lavage cells was counted by cell counter (Coulter Counter; Coulter, Hialeah, FL). Cytospin slides were stained with Leukostat (Fisher Diagnostics, Pittsburgh, PA) and differential cell counts were performed in a blinded fashion, counting at least 300 cells under light microscopy.
Cytokine (IL-4, IL-5, and IFN-) levels in BALF supernatants were
measured by ELISAs as described (18) and IL-10, IL-12
(p70), and IL-13 were assayed by ELISA (R&D Systems, Minneapolis, MN)
according to the manufacturer’s recommendations. Cytokine levels were
determined by comparison with known standards. The limit of detection
was 4 pg/ml.
Measurement of serum anti-OVA Ab and total Ig levels
Anti-OVA IgE Ab levels were measured by ELISA, as previously described (19), 48 h after the last airway challenge. The Ab titers of the samples were related to pooled standards that were generated in the laboratory and expressed as ELISA units per milliliter. Total IgE levels were determined using the same method compared with a known mouse IgE standard (BD PharMingen, San Diego, CA). The limit of detection was 100 pg/ml for IgE.
Abs and T cell depletion
Monoclonal anti-murine TCR- Ab (H57-597) was described
previously (20). Monoclonal anti-murine TCR- Abs
(GL3 and 403A10) that were panspecific for TCR- were gifts from Drs.
L. LeFrançois (University of Connecticut, Farmington, CT)
(21) and S. Tonegawa (Massachusetts Institute of
Technology, Cambridge, MA) (22). The dose administered was
optimized for depletion and routinely depleted >90% of splenic and
pulmonary T cells (10). mAbs were prepared from
Ab-secreting hybridoma cell lines. These mAbs were purified on affinity
columns and quantified.
Depletion was achieved after injection of 200 µg hamster IgG mAb
anti-TCR- (1:1 mixture of GL3 and 403A10) into the tail vein 3
days before the first OVA challenge (21). Sham depletion
was conducted using hamster IgG (The Jackson Laboratory).
T cell purification and FACS analysis
Lung cells were isolated as previously described (23) and passed through nylon wool columns to yield an enriched T cell preparation containing >90% CD3+ cells as previously described (24).
For cytofluorographic analysis, mAbs were conjugated with N-hydroxysuccinimido-biotin (Sigma-Aldrich) and/or FITC isomer I on Celite (Sigma-Aldrich) and analyzed on an XL2 cytofluorograph (Coulter, Miami, FL). Streptavidin-PE (diluted at 1/100 per 1 x 106 cells; BioSource International, Camarillo, CA) was used for the biotin-conjugated Abs to enhance detection as described (25).
Histologic and immunohistochemistry studies
After obtaining the BALF, lungs were inflated through the tracheal tube with 2 ml air and fixed in 10% formalin. Portions of lung tissue were cut around the main bronchus and embedded in paraffin blocks. Tissue sections (5 µm thick) were cut, deparaffinized, and then stained with H&E and examined under light microscopy. The examiner was blinded as to treatment group.
Cells containing major basic protein (MBP) in lung sections were identified by immunohistochemical staining and quantitated as described using a rabbit anti-mouse MBP (provided by Dr. J. J. Lee, Mayo Clinic, Scottsdale, AZ) (23).
Statistical analysis
Values for all measurements were expressed as the mean ± SEM. Student’s two-tailed unpaired t test was used to determine the levels of difference between two experimental groups. ANOVA was used to compare percentage changes of RL and Cdyn between different groups with the same treatment. The values for significance were set at p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TNF- exerts its activities by interacting with two functionally
distinct receptors, p55 and p75, which are independently expressed on
the cell surface. To determine the importance of TNF- receptors in
the development of allergen-induced AHR, we monitored airway
responsiveness to inhaled MCh in p55-deficient and p75-deficient mice.
There was no significant difference in RL and Cdyn between
C57BL/6 (wild-type (WT)) mice and p55- and p75-deficient mice exposed
to OVA alone (challenge alone) (Fig. 1
).
After OVA sensitization and challenge, p55-deficient mice failed to
develop AHR, whereas p75-deficient mice developed AHR similar to WT
C57BL/6 mice (Fig. 1). These results indicate that the TNFRs p55 and
p75 play different roles in the development of allergen-induced
AHR.
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The number and types of inflammatory cells in the airways of
TNFR-deficient mice were measured in BALF. In mice that underwent OVA
challenge alone, very few inflammatory cells were detected (Fig. 2A). Sensitization and
challenge with OVA resulted in a marked increase in the number of
eosinophils in the BALF, although the number of eosinophils in the
p75-deficient mice and especially p55-deficient mice were significantly
lower than in WT mice. Nonsensitized but OVA-challenged p75-deficient
mice had an increased number of lymphocytes in BALF compared with
p55-deficient and WT mice (Fig. 2A).
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B). Cytokine levels in p55-deficient and p75-deficient mice
Concentrations of inflammatory cytokines in BALF supernatants were
measured by ELISA. After OVA sensitization and challenge, IL-4, IL-5,
IL-10, and IL-13 levels in BALF increased significantly compared with
mice challenged alone in all three groups of mice. IL-4 levels were not
significantly different in p55- or p75-deficient mice or WT controls
(Fig. 3A). IL-5 levels in
p55-deficient mice were significantly lower than in the WT controls and
p75-deficient mice (Fig. 3B). IL-10 levels increased
similarly in all three groups after sensitization and challenge
(Fig. 3C) and IL-13 levels paralleled those of IL-5, with
the p55-deficient mice showing thesmallest increase (Fig. 3E). For each group, OVA sensitization and challenge also
resulted in an increase in IL-12 (Fig. 3D) and IFN- (Fig. 3F) levels compared with animals challenged alone, but both
IFN- and IL-12 levels were lower in the p55-deficient than in the WT
or p75-deficient mice. These results indicate that the absence of the
p55 receptor impacts the levels of both Th1 and Th2 cytokines.
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Anti-OVA IgE Ab levels were measured by ELISA 48 h after the
last airway challenge. Anti-OVA IgE and total IgE levels in the serum
of OVA-sensitized and -challenged WT mice, p55- and p75-deficient mice
were not significantly different from one another (Table I).
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T cells and T cells in TNFR-deficient mice
The numbers of T cells and T cells in the lungs were
analyzed (Fig. 4). Numbers of nylon wool
nonadherent T cells in the lungs of p55-deficient mice were
significantly lower when compared with WT and p75-deficient mice. The
number of T cells in the lungs of TNFR p75-deficient mice was
significantly increased compared with the other mice. Treatment with
anti-TCR- mAb not only decreased the numbers of T cells
in all groups of mice but also resulted in increased numbers of
T cells in sensitized and challenged p75-deficient mice.
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T cell depletion restores airway responsiveness in
p55-deficient mice
We previously demonstrated that T cells play a
negative regulatory role in the development of AHR (10)
and that TNF- negatively regulated AHR through T cells
(11). Therefore, we examined whether T cells
play a role in the failure of p55-deficient mice to develop AHR. As
shown in Fig. 4, anti- treatment effectively eliminated T
cells in all three groups of mice. WT mice showed an increase in AHR
after T cell depletion, confirming previous results
(10) (Fig. 5). p55-deficient
mice treated with anti-TCR- developed significant AHR after OVA
sensitization and challenge; the levels were similar to untreated WT
mice. In contrast, p75-deficient mice administered anti-TCR-
failed to show any differences in the level of AHR compared with
nontreated mice.
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treatment on AHR was not associated with
changes in cellular inflammatory response
In anti-TCR--treated, OVA-sensitized and -challenged
p55-deficient mice, which now demonstrated AHR, there was no
significant difference in the composition of inflammatory cells in BALF
as a result of T cell depletion (Fig. 6). The lower number of eosinophils seen
in p55-deficient mice after sensitization and challenge (Fig. 2) was
still evident (and even lower) after T cell depletion, despite
the development of AHR.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is not well defined
(3, 4, 5, 6, 7). In this paper we demonstrate that OVA-sensitized
and -challenged p75-deficient mice developed AHR to a similar degree as
WT mice but p55-deficient mice failed to develop AHR. Such data confirm
that the two TNFRs play distinct roles in the development of AHR, and
this may be the result of the induction of different airway
inflammatory pathways. The data indicate that eosinophil numbers in
BALF in both the p55- and p75-deficient mice after OVA sensitization
and challenge were lower than in WT mice, but the number of eosinophils
in p55-deficient mice was even further decreased compared with
p75-deficient mice. The p55 receptor appears to play an important role
in the up-regulation of endothelial cell adhesion molecule expression
at the sites of allergen challenge, as evidenced by studies
demonstrating reduced eosinophil rolling and adhesion and accumulation
in the BALF in allergen-challenged p55- and p55/p75-deficient mice
(26). In p55-deficient mice, the levels of both IL-5 and
IL-13 in BALF were significantly lower compared with sensitized and
challenged WT mice and p75-deficient mice; in p75-deficient mice there
were no significant differences compared with WT mice. Moreover, both
IFN- and IL-12 levels in the p55-deficient mice after sensitization
and challenge were significantly lower than those in controls, and IL-4
and IL-10 levels in both p55-deficient mice and p75-deficient mice were
not significantly different from WT mice. These results and the failure
to develop AHR in sensitized and challenged p55-deficient mice indicate
that TNFR1 plays an important role in regulating Ag-induced Th2
cytokine production (IL-5 and IL-13), Th1 cytokine production (IFN-
and IL-12), eosinophil and lymphocyte recruitment to the lung, and
airway function. In the absence of the p75 receptor there appeared to
be fewer consequences.
Independent expression on cells (27, 28), DNA analysis
(1, 2, 29), and lack of homology of the
intracellular domains (30) suggest that the two receptors
should be responsible for inducing divergent cellular responses. TNFR
p75 exhibits greater specificity and higher affinity in its
interactions with TNF- than does the p55 receptor (31).
It has been proposed that, at low concentrations of TNF, p75 functions
as a catcher by binding TNF and delivering it to the p55 receptor
(32). Unlike p55, p75 seems to function in transmitting
activating signals for apoptosis (31, 32, 33, 34). The murine p55
receptor binds both murine and human TNF- while the murine p75
receptor binds only its homologous murine ligand and not the human
protein (35, 36). Furthermore, recent experiments using
p55-deficient mice have demonstrated that the p55 TNFR plays a
physiologically important role in promoting lethal shock induced by LPS
and galactosamine and in effecting antimicrobial responses to
Listeria monocytogenes (7, 37). By
comparison, little information is available concerning the biologic
responses mediated by the p75 TNFR. In vivo experiments have suggested
that the p75 receptor enhances p55-induced biologic responses by
facilitating binding to p55 (38). In addition, p75 induces
proliferative responsiveness in certain cells of hematopoietic origin
and enhances expression of certain adhesion molecules such as ICAM-1
(4, 32). The underlying mechanisms are not known, but
growing evidence now suggests that most of the biologic effects TNF-
exerts on airway smooth muscle are mediated by the p55 receptor
(9).
T cells in mice and humans respond more strongly to TNF- than
do T cells (12). The stronger response of T
cells to TNF- depends on the presence of p75 and is correlated with
higher inducible expression levels of TNFR p75 in these cells
(12). Although T cells in allergic inflammation are
essential contributors to increased AHR (10), we have
found that T cells can exhibit negative regulatory effects on
AHR, and we proposed that T cells exhibit different responses in
the lung depending on the type of stimulus (10). In this
study, we investigated the numbers of T cells and T cells
in the lungs of p55- and p75-deficient mice. Numbers of T cells
in the lungs of p55-deficient mice were significantly lower when
compared with those in the lungs of WT or p75-deficient mice. It thus
appears that the p55 pathway is also central in the normal development
of the allergic T cell response. In contrast, numbers of
T cells in the lungs of p75-deficient mice were significantly increased
as compared with thosein the lungs of WT (2.2-fold higher) or
p55-deficient (3.2-fold higher) mice, implying that the p75 pathway is
also responsible for negative regulatory effects of TNF- on T
cell expansion.
Consistent with our earlier studies (10, 11), we found
that depletion of T cells (by in vivo Ab treatment) resulted in
increased AHR. This effect was most notable in the p55-deficient mice,
where effects of TNF- are exclusively mediated via the p75 pathway;
increased AHR was also noted in the WT mice to a lesser extent
(10, 11). Presumably, TNF- activated the T cells
(12), effectively preventing development of AHR, an effect
independent of the inflammatory response. The absence of such an effect
in p75-deficient mice further implies that the p75 pathway is required
for the regulatory function of T cells. This same pathway also
appears to shape the development of pulmonary T cells and their
response to OVA, as indicated by the increase in T cells when it
is absent. However, not all regulatory functions of T cells
depend on TNF- and the p75 pathway in particular. In vivo treatment
with anti-TCR- mAb showed that T cells can prevent or
negatively impact the development of the allergic T cell
response, and this effect was least prominent with the enlarged T cell
population in the p75-deficient mice. Therefore, the p75 pathway not
only may lead to activation of certain T cells but may also hold
in check, perhaps through induction of apoptosis, the expansion of
these cells, as seen in the p75-deficient mice. In the p75-deficient
mice, despite the increase in numbers of pulmonary T cells,
their presence or depletion had little effect on development of AHR,
consistent with a failure of their activation or differences in
T cell subset distribution.
In summary, this study demonstrates complex contributions of the
TNF- receptors, p55 and p75, to the overall regulation of allergic
inflammatory responses in the lung and the development of altered
airway function. TNF- interacts with T cells primarily
through the p75 receptor pathway, and this interaction is associated
with a down-regulation of AHR. In the absence of this pathway there is
expansion of pulmonary T cells as well as normal development of
AHR despite the increase in numbers. In contrast, the p55 receptor may
be required for development of AHR and airway inflammation, and the
interplay of both receptor-driven pathways shapes the allergic airway
response and the mechanisms that control it.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Erwin W. Gelfand, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail address: gelfande{at}njc.org
3 Abbreviations used in this paper: AHR, airway hyperresponsiveness; BALF, bronchoalveolar lavage fluid; Cdyn, dynamic compliance; RL, lung resistance; MCh, methacholine; WT, wild type; MBP, major basic protein.
Received for publication June 7, 2002. Accepted for publication August 8, 2002.
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  L. Cook, N. Miyahara, N. Jin, J. M. Wands, C. Taube, C. L. Roark, T. A. Potter, E. W. Gelfand, R. L. O'Brien, and W. K. Born Evidence That CD8+ Dendritic Cells Enable the Development of {gamma}{delta} T Cells That Modulate Airway Hyperresponsiveness J. Immunol., July 1, 2008; 181(1): 309 - 319. [Abstract] [Full Text] [PDF]
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 A. G. P. Guedes, J. A. Jude, J. Paulin, H. Kita, F. E. Lund, and M. S. Kannan Role of CD38 in TNF-{alpha}-induced airway hyperresponsiveness Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L290 - L299. [Abstract] [Full Text] [PDF]
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N. Jin, C. Taube, L. Sharp, Y.-S. Hahn, X. Yin, J. M. Wands, C. L. Roark, R. L. O'Brien, E. W. Gelfand, and W. K. Born Mismatched Antigen Prepares {gamma}{delta} T Cells for Suppression of Airway Hyperresponsiveness J. Immunol., March 1, 2005; 174(5): 2671 - 2679. [Abstract] [Full Text] [PDF]
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Y.-S. Hahn, C. Taube, N. Jin, L. Sharp, J. M. Wands, M. K. Aydintug, M. Lahn, S. A. Huber, R. L. O'Brien, E. W. Gelfand, et al. Different Potentials of {gamma}{delta} T Cell Subsets in Regulating Airway Responsiveness: V{gamma}1+ Cells, but Not V{gamma}4+ Cells, Promote Airway Hyperreactivity, Th2 Cytokines, and Airway Inflammation J. Immunol., March 1, 2004; 172(5): 2894 - 2902. [Abstract] [Full Text] [PDF]
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