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1+ T Cells Suppress and V4+ T Cells Promote Susceptibility to Coxsackievirus B3-Induced Myocarditis in Mice1
*
Department of Pathology, University of Vermont, Burlington, VT 05446;
Department of Biology, University of Colorado, Colorado Springs, CO 80933; and
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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mice, which are
C57BL/6 mice transgenically induced to express IE Ag, develop
significant myocarditis upon Coxsackievirus B3 infection. Despite this
difference in inflammatory damage, cardiac virus titers are similar
between C57BL/6 and Bl.Tg.E mice. Removing 
T cells from
either strain by genetic manipulation ( knockout(ko)) changes the
disease phenotype. C57BL/6 ko mice show increased myocarditis.
In contrast, Bl.Tg.E ko mice show decreased cardiac
inflammation. Flow cytometry revealed a difference in the cell
subsets in the two strains, with V1 dominating in C57BL/6 mice, and
V4 predominating Bl.Tg.E mice. This suggests that these two
V-defined subsets might have different functions. To test this
possibility, we used mAb injection to deplete each subset. Mice
depleted of V1 cells showed enhanced myocarditis, whereas those
depleted of V4 cells suppressed myocarditis. Adoptively transfusing
enriched V4+ cells to the C57BL/6 and Bl.Tg.E
ko strains confirmed that the V4 subset promoted myocarditis. Th
subset analysis suggests that V1+ cells biased the
CD4+ T cells to a dominant Th2 cell response, whereas
V4+ cells biased CD4+ T cells toward a
dominant Th1 cell response. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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to
myocarditis-resistant mice infected with a myocarditic Coxsackievirus
B3 (CVB3)3 variant
restored disease susceptibility. This laboratory has demonstrated that
myocarditis susceptibility additionally depends upon activation of T
cells expressing the TCR (9, 10, 11, 12).
T cells can be defined by the type of TCR they express. Most
Ag-specific T cells have a TCR consisting of an - and a
ß-polypeptide chain. In the periphery, a small proportion of T cells
express a receptor consisting of a and a polypeptide chain.
Although the role of ß+ T cells in most
immunological diseases is clear, the role for
+ T cells is usually more obscure.
+ T cells often accumulate at sites of
inflammation, whether caused by viral (13, 14, 15), bacterial
(16), or parasite (17, 18). In some cases,
these responses are subdivided by variable (V) gene expression of the
- and -chains, such that there are distinct patterns of
infiltration into inflammation sites depending upon the disease
(17, 19, 20, 21, 22). This suggests that only specific
+ cell populations may participate in
disease processes. How + cells participate
in disease is also complex, as both beneficial and detrimental roles
have been attributed to these cells in various experimental models
(23, 24, 25, 26). Previously, we have demonstrated that different
subpopulations of + T cells, based on their
V/V use, were activated in the resistant (C57BL/6) vs the
susceptible (Bl.Tg.E) mouse strain following infection with CVB3,
with V1 cells dominating in the former and V4 cells dominating in
the latter strain. In this paper, we show that the different
+ cell populations are selectively
responsible for both disease resistance and susceptibility. Thus, cells
expressing the V1 gene suppress myocarditis, while cells expressing
the V4 gene promote disease. This is the first demonstration we
could find that in the same disease model different
+ cell subpopulations had both beneficial
and detrimental effects.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 and C57BL/6J-Tcrdtm1Mom (C57BL/6
knockout (ko)) mice were purchased from The Jackson Laboratory
(Bar Harbor, ME) as breeder pairs. Breeding pairs of transgenic
C57BL/6 mice expressing the MHC class II Ek
gene from A/J mice (IA+IE+;
Bl.Tg.E strain) were initially obtained from Dr. Chella David
(Department of Immunology, Mayo Clinic, Rochester, MN).
Characterization and description of these mice has been published
previously (12, 27). Bl.Tg.E mice lacking
+ T cells were produced by mating
Bl.Tg.E male to C57BL/6 ko females, backcrossing the
F1 progeny to the C57BL/6 ko parental strain
for seven generations, and screening for IEk+
progeny using cytometric analysis of PBLs. IEk+
male and female mice were inbred for a further six generations. All
progeny are screened for IEk expression
(Bl.Tg.E ko strain).
Virus, virus infection, and virus titration
Animals were infected by i.p. injection of 0.5 ml PBS containing 104 PFUs of CVB3 (H3 variant), derived from Cos cells transfected with the infectious cDNA of this virus (28). For virus titration, hearts were homogenized in 0.9 ml RPMI 1640 containing 100 U/ml penicillin, 100 µg/ml streptomycin, and 5% FBS. Cellular debris was removed by centrifugation at 1045 x g for 10 min. The supernatant was titered by the plaque-forming assay on HeLa cell monolayers as described previously (29).
Antibodies
Ab class control (isotype control) and Ag-specific Abs were
obtained from PharMingen (San Diego, CA). These included the following:
purified rat anti-mouse CD16/CD32 (Fc Block; clone 2.4G2);
Cy-Chrome, FITC, and PE-rat IgG1 (clone R3-34); biotinylated and PE-rat
anti-mouse IFN- (clone XMG 1.2); biotinylated and PE-rat
anti-mouse IL-4 (clone BVD4-1D11); Cy-Chrome-rat-anti-mouse CD4
(clone GK 1.5), purified mouse-anti-IAb
(clone AF6-120.1); PE-mouse-anti-IEk (clone
14-4-4S); purified hamster anti-TCRß (clone H57-597); purified
mouse anti-NK1.1 (clone PK136); FITC and PE-hamster IgG; FITC and
PE-hamster-anti- TCR (clone GL3); and purified mouse
anti-hamster IgG (clones G70-204/G94-56) Abs. Additional purified
FITC- and biotin-conjugated Abs to V1 (clone 2.11) and V4 (clone
UC3) were prepared and tested in the laboratory of Dr. Rebecca O’Brien
(National Jewish Medical and Research Center, Denver, CO). Cy-Chrome,
FITC, and PE-conjugated streptavidin were purchased from
PharMingen.
Isolation of lymphocyte populations
For isolation of + T cells, mice
were euthanized by injecting 120 mg/kg sodium pentobarbital in PBS i.p.
The spleens were removed, disrupted to produce single cell suspensions,
and washed in RPMI 1640 medium containing 5% FBS and antibiotics.
After removing tissue debris by sedimentation, the cells were
centrifuged at 225 x g for 10 min at 5°C. The cell
pellet was resuspended in medium, layered over Histopaque-1077 (Sigma,
St. Louis, MO), and centrifuged at 1048 x g for 15
min, and the lymphoid cells at the interface were retrieved. After
washing the cells in medium with 5% FBS, they were incubated
for 30 min on nylon wool columns containing 0.5 g nylon wool
(Polysciences, Warrington, PA) at 37°C. The nonadherent cells
were retrieved by washing the column with 30x void volume of medium.
The cells were resuspended in medium and counted by trypan blue
exclusion. For every 106 lymphocytes in 100 µl
medium with 5% FBS, 1 µl each of FcBlock, anti-ß TCR,
anti-IAb, and anti-NK1.1 were added to
the cell suspension. The cells were incubated for 20 min at 4°C on a
rocker platform, washed once, and resuspended in medium 1:100 dilution
of mouse anti-hamster IgG for 20 min at 4°C. The cells were then
washed once more and incubated with magnetic particles conjugated with
anti-mouse IgG (PerSeptive Biosystems, Framingham, MA) for 30 min
at 4°C. The cell suspension was passed twice over a magnet
(PerSeptive Biosystems) to remove Ab-bound cells. This produced a cell
population containing 
50% + T cells as
determined by staining with PE-anti- TCR Ab. To improve the
purity of the cell population further, and isolate the specific V4
subpopulation, the cells were stained with PE-anti- TCR and
biotinylated hamster anti-V4 mAb for 20 min, washed, and
incubated with FITC-streptavidin for 20 min at a 1:50 dilution. After
washing, the cells were resuspended in PBS/2% BSA and sorted in a
Coulter (Palo Alto, CA) Epics Elite flow cytometer into RPMI 1640
containing 20% FBS as described below. Flow diagrams of the initial
(Fig. 1
A), positively selected
(Fig. 1B), and residual (Fig. 1C) populations are
given for + cells stained for the V4
receptor. For adoptive transfer, a total of 2.1 x
106 V4+ cells were
isolated from 35 pooled spleens (initial starting population after
nylon wool of 6.9 x 108 lymphocytes).
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For preparation of PBLs, blood was obtained by cardiac puncture at the time of euthanization, using a 26 gauge needle and a 1-cc syringe containing 50 µl of a 0.15% EDTA (Sigma) solution. The blood was diluted 1:10 with medium, layered on Histopaque, and centrifuged at 1048 x g for 15 min. The lymphoid cells at the interface were removed, washed once, and counted by trypan blue exclusion.
Flow cytometry
For cell surface marker staining, 1 x 105 lymphocytes were washed in PBS containing 1% BSA and 0.1% sodium azide (PBS-BSA) and resuspended in 0.1 ml PBS-BSA containing a 1:100 dilution of fluorochrome-labeled Ab and a 1:100 dilution of Fc-Block. After incubation for 30 min on ice, the cells were washed twice in PBS-BSA, and fixed in 2% formaldehyde for flow analysis.
For intracellular cytokine staining, a modification of the method of
Picker et al.(30) was used to evaluate intracellular
cytokines in splenocytes. Briefly, 1 x 106
spleen cells were cultured in medium containing 10 µg/ml brefeldin A,
50 ng/ml PMA, and 500 ng/ml ionomycin (Sigma) for 4 h at 37°C in
5% CO2. The cells were subsequently resuspended
in medium containing 50 µg/ml rat polyclonal IgG (Zymed, San
Francisco, CA) and brefeldin A, incubated for 10 min at 5°C, washed,
and resuspended in medium containing Fc-Block (PharMingen) and either
fluorochrome-labeled surface marker Abs or appropriate Ig isotype
controls. After incubation on ice for 30 min, the cells were washed in
PBS-BSA-brefeldin A, and fixed for 10 min in 2% paraformaldehyde. The
cells were then washed once in PBS-BSA buffer, incubated for 10 min in
PBS-BSA buffer containing 0.5% saponin, and stained for intracellular
cytokines using either FITC-anti-IFN- and PE-anti-IL-4. As an Ab
class control for the intracellular staining, we used PE-rat IgG. All
staining was performed in buffer containing Fc-Block and 50 µg/ml
polyclonal rat IgG to block nonspecific Ab binding. After incubation
for 30 min, the cells were washed twice in PBS-BSA-saponin and once in
saponin-free PBS to close the membrane, then resuspended in PBS/azide
containing 2% paraformaldehyde. Positive controls for cytokine
staining were 2.5 x 105 of either MIC-1-
(IFN-) and MIC-2 (IL-4)-fixed cells obtained from PharMingen.
Control cell populations were permeabilized and stained as described
above.
Stained cell populations were analyzed using a Coulter Epics Elite
instrument with a single excitation wavelength (488 nm) and band
filters for PE (575 nm), FITC (525 nm), and Cy-Chrome (670 nm). Each
sample population was classified for cell size (forward scatter) and
complexity (side scatter), then gated on a population of interest. At
least 10,000 cells were evaluated for each sample. Criteria for
positive staining were established using isotype controls. Generally,
the results were expressed as the percentage of gated cells which
stained positively for each marker, or as the percentage of positive
cells after gating using an additional marker, after subtracting the
percent positive cells in the Ab class control. For example, the
percentage of CD4+ cells in peripheral blood
staining for IL-4 represents the following:
(CD4+/IL-4+
cells)/(CD4+/IL-4- and
CD4+/IL-4+ cells) x 100. In some cases
(Fig. 3 and Table II), values may represent the percent of the total
cell population staining for specific markers. Each study was repeated
at least two times, and the data from a representative experiment are
presented.
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Hearts were removed, fixed in 10% buffered formalin, paraffin embedded, sectioned, and stained with von Kossa. Stained sections were used for image analysis in transmitted light mode with an Olympus (New Hyde Park, NY) BX50 compound light microscope (x4 objective lens; numerical aperture, 0.13). True color digital images (640 by 480 pixels) were captured with a Sony (Tokyo, Japan) DXC-960 MD/LLP video camera connected via an RS170 cable to a video frame grabber on a Sun SPARCstation 5 (Mountain View, CA). Image processing and analysis were accomplished with IMIX software (Princeton Gamma Tech, Princeton, NJ). Final percent cardiac injury was calculated by dividing the area of injury by the total area of the heart.
Statistics
Statistical evaluation was performed using the Wilcoxon ranked score method.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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+ T cells modulate myocarditis susceptibility
C57BL/6, C57BL/6 ko, Bl.Tg.E, and Bl.Tg.E ko
mice were infected with CVB3 and euthanized 7 days later. Hearts were
evaluated for myocardial inflammation (Table I and Fig. 2) and cardiac virus titers (Table I).
PBLs were evaluated for CD4+ cells,
IL-4+, and IFN-+ cells
using intracellular cytokine staining and flow analysis. For this
evaluation, PBLs were surface stained for CD4 (Cy-Chrome) and
intracellularly stained for IFN- (FITC) and IL-4 (PE). Fig. 3
provides a flow diagram for one animal
(highlighted in bold in Table I) from each group. In Fig. 3, the
numbers in the upper right corner represent the total percent of all
cells in each quadrant. Table I provides the individual animal values
for myocarditis, cardiac virus titers, percent of
CD4+ cells in the peripheral blood staining
intracellularly for either IFN- or IL-4, and the calculated ratio of
CD4+ Th1/Th2 cells. As can be seen in Fig. 3, while CD4+ cells clearly stain for either IFN-
or IL-4, non-CD4+ cells are also cytokine
positive in most animals. The identity of
non-CD4+ cells staining for cytokine has not been
determined.
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mice,
transgenic C57BL/6 mice that express MHC class II IE Ag, in contrast,
are myocarditis susceptible with approximately six times more cardiac
inflammation than wild-type animals. As can be seen in Table I,
removing + T cells reversed this pattern (i.e.,
C57BL/6 ko mice showed higher levels of myocarditis, whereas
B1.Tg.E ko mice had lower levels). This suggests that
+ T cells are involved in both protection and
promotion of cardiac inflammation. C57BL/6 ko mice had fewer Th2
(CD4+/IL-4+) but more Th1
(CD4+/IFN-+) cells than C57BL/6 mice
(p < 0.05). In contrast, B1.Tg.E ko mice showed
significantly more Th2 cells than B1.Tg.E animals, but fewer Th1
cells. This suggests that + cells might be directly
or indirectly modulating Th cell phenotype.
Evaluation of subpopulations of + T cells in
myocarditis
Previous studies showed that V1+ cells
dominate among + T cells in the hearts of
CVB3-infected C57BL/6 mice while V4+ cells
dominate in the hearts of infected Bl.Tg.E animals. To evaluate
whether V populations might differentially affect myocarditis
susceptibility, C57BL/6 and Bl.Tg.E mice were depleted of each
subset by injecting either 100, 200, or 400 µg anti-V1 or
anti-V4 Abs i.v. through the tail vein. Three days later, the
mice were injected i.p. with CVB3. Seven days after infection, mice
were killed. PBLs were evaluated by intracellular cytokine staining for
Th1 and Th2 cells (Table II, Fig. 3).
Splenocytes were evaluated first for the percentage of total
splenocytes which are + and either
V1+ or V4+ (Table II). Secondly, flow was gated on the +
population and evaluated for V1+ or
V4+ cells (Fig. 4). +
constitute a small subpopulation of total splenocytes. Gating
specifically on the + cell population can
better demonstrate the effectiveness of Ab depletion. The heart was
processed for histology (Table II, Fig. 2). Ab depletion was effective,
especially at the 400-µg dose, in reducing the number of
V1+ or V4+ cells
invivo. Anti-V4 treatment of Bl.Tg.E mice resulted in reduction
of myocarditis (Table II) and an increase in CD4+
Th2 cells in peripheral blood. Anti-V1 Ab treatment produced the
opposite result, a modest increase in myocarditis and decrease in
CD4+Th2 cells.
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4+ cells in CVB3
myocarditis, C57BL/6 and Bl.Tg.E mice lacking
+ cells were reconstituted with
V4+ cells purified from day 7 CVB3-infected
Bl.Tg.E mice by sterile sorting. Lymphocytes were retrieved from the
spleens and enriched for + cells as
described in Materials and Methods. Fig. 1 shows flow
cytometric analysis of the V4+ cell population
before and after purification. C57BL/6 ko and Bl.Tg.E
ko mice were infected with CVB3 and injected i.v. with either
102, 104, or 2.5 x
105 of these cells 1 day later. All animals were
killed 7 days after infection. Table III
shows the effect of the + cell transfer on
myocarditis. Giving V4+ cells to either
Bl.Tg.E ko or C57BL/6 ko mice resulted in enhanced
myocarditis. Aliquots of the V4+ cells
were stimulated with PMA and ionomycin for 4 h in the presence of
brefeldin A, then intracellularly stained with either
Cy-Chrome-streptavidin and biotinylated anti-IFN- or
anti-IL-4 to evaluate cytokine production (Fig. 5). V4+ cells
stained for IFN- but not for IL-4.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1+ T cells suppress myocardial inflammation
whereas V4+ T cells promote disease. Thus the
type of + cell dominating, or responding in
an animal will determine its disease susceptibility or resistance. We
believe that this is the first study to demonstrate distinct roles for
different + T cell subpopulations within
the same disease. The mechanism of + cell
regulation seems to be mediated through effects on Th subset response
because Th2 cell responses, for the most part, correlate with
V1+ cell dominance and Th1 cell responses
correlate with dominant V4+ cells. Th1/Th2
dichotomy in disease susceptibility and resistance is well-recognized
(31, 32, 33, 34, 35, 36). In diseases dependent on cellular inflammation
and pro-inflammatory cytokines such as IL-1 and TNF, it is
reasonable that Th1 cell responses should be pathogenic while Th2 cell
responses should be protective. This is especially true in CVB3-induced
myocarditis, because T cell-dependent responses are not required for
virus clearance (37) and, therefore, are not
"beneficial" in terms of the infection itself. How
+ cells modulate Th1/Th2 responses has not
been thoroughly addressed in this communication, although we show that
V4+ cells which promote Th1 cell responses do
produce IFN-. Th cell modulation by +
cells has been reported previously (38, 39), and
presumably occurs through cytokines released by these effectors. IL-4
would promote Th2 cell differentiation if present early in the
Ag-specific T cell response, while IFN- directly or indirectly would
promote Th1 cell responses (31, 40). Other possible
mechanisms for + cell-induced
immunomodulation are possible. One such mechanism could be direct
killing of specific CD4+ Th cells by
+ lymphocytes. Evidence supporting
selective + cell lysis of
CD4+ lymphocytes comes from studies in Lyme
arthritis (26) and from CVB3-induced myocarditis
(12). In the latter studies, +
cells directly killed differentiated Th2 cell lines through
Fas-dependent mechanisms. What structural differences between Th1 and
Th2 cells allow + cell recognition and/or
killing of the Th2 but not the Th1 cells is not known. It is equally
possible that + cells recognize both Th1
and Th2 cells, but the Th1 cells are rescued from death while the Th2
cells are not. Certainly, T cell apoptosis can be abrogated with
appropriate positive signals (31). An additional
possibility is that + cells influence other
cell types, such as macrophage, which subsequently alter Th development
(41).
Experiments were performed with both direct Ab-induced depletion of
+ cells in vivo and by adoptive transfer of
positively sorted + cell subpopulations
into genetically + cell-deficient
recipients. Both sets of experiments indicate a role for specific
+ subpopulations in regulating both Th cell
phenotype and myocarditis susceptibility. Because Ab binding to the TCR
might activate cells to release cytokines or immunomodulate
ß+ T cell responses before their
elimination, the Ab depletion experiments might indicate either that
the lack of or activation of specific subpopulations resulted in the
observed effects. However, specific V4 Abs were used to isolate
purified subpopulations for adoptive transfer. Although these Abs might
also have activated the respective cell populations,
V4+ cells continued to promote myocarditis
susceptibility and Th1 responsiveness.
An important question is why dominant V populations differ between
genetic strains of mice. Various studies have shown that class II MHC
molecules influence + cell subpopulation
composition (12, 42, 43, 44). C57BL/6 mice inherently lack MHC
class II IE Ag expression due to a naturally occurring mutation in
their E gene, while Bl.Tg.E mice express IE (27).
Flow cytometric analysis of + cell
populations in the spleens of uninfected C57BL/6 mice show 50% of
these cells express V1 and 20% express V4 receptors, whereas in
uninfected Bl.Tg.E mice, 40% of +
cells express V4 and only 35% express V1 receptors. Thus, the
uninfected mice from each strain have the same propensity for
differential V subset expression as infected mice. This suggests
that predominance of distinct V subpopulations in myocarditis in
C57BL/6 and Bl.Tg.E mice reflects the inherent influence of MHC
class II Ag on clonal selection of V subpopulations during thymic
development.
The importance of our study is that it shows the complexity of
+ cell interactions in immunological
disease. As with T cells expressing the ß+
TCR, where different subpopulations might interact negatively or
positively with each other, + cell
subpopulations may also interact between themselves and also with the
ß+ cells. The +
cell plays an intricate and critical role in the pathogenesis of at
least some diseases. How universally important they might be in other
forms of disease will require further investigation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Sally Ann Huber, University of Vermont, Department of Pathology, College of Medicine, 55A Sooth Park Drive, Colchester, VT 05446.
3 Abbreviations used in this paper: CVB3, Coxsackievirus B3; V, variable; ko, knockout.
Received for publication January 4, 2000. Accepted for publication July 17, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cells in acute Plasmdium falcifarum malaria. Immunol. Lett. 25:139.[Medline]
T cell receptor variable region usage during the development of experimental allergic encephalomyelitis. J. Neuroimmunol. 62:1.[Medline]
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E. M. Andrew, D. J. Newton, J. E. Dalton, C. E. Egan, S. J. Goodwin, D. Tramonti, P. Scott, and S. R. Carding Delineation of the Function of a Major {gamma}{delta} T Cell Subset during Infection J. Immunol., August 1, 2005; 175(3): 1741 - 1750. [Abstract] [Full Text] [PDF]
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 S. A. Huber and D. Sartini Roles of Tumor Necrosis Factor Alpha (TNF-{alpha}) and the p55 TNF Receptor in CD1d Induction and Coxsackievirus B3-Induced Myocarditis J. Virol., March 1, 2005; 79(5): 2659 - 2665. [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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M. K. Aydintug, C. L. Roark, X. Yin, J. M. Wands, W. K. Born, and R. L. O'Brien Detection of Cell Surface Ligands for the {gamma}{delta} TCR Using Soluble TCRs J. Immunol., April 1, 2004; 172(7): 4167 - 4175. [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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J. E. Dalton, J. Pearson, P. Scott, and S. R. Carding The Interaction of {gamma}{delta} T Cells with Activated Macrophages Is a Property of the V{gamma}1 Subset J. Immunol., December 15, 2003; 171(12): 6488 - 6494. [Abstract] [Full Text] [PDF]
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J. F. Hedges, J. C. Graff, and M. A. Jutila Transcriptional Profiling of {gamma}{delta} T Cells J. Immunol., November 15, 2003; 171(10): 4959 - 4964. [Full Text] [PDF]
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Y.-S. Hahn, C. Taube, N. Jin, K. Takeda, J.-W. Park, J. M. Wands, M. K. Aydintug, C. L. Roark, M. Lahn, R. L. O'Brien, et al. V{gamma}4+ {gamma}{delta} T Cells Regulate Airway Hyperreactivity to Methacholine in Ovalbumin-Sensitized and Challenged Mice J. Immunol., September 15, 2003; 171(6): 3170 - 3178. [Abstract] [Full Text] [PDF]
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 Y. Gao, W. Yang, M. Pan, E. Scully, M. Girardi, L. H. Augenlicht, J. Craft, and Z. Yin {gamma}{delta} T Cells Provide an Early Source of Interferon {gamma} in Tumor Immunity J. Exp. Med., August 4, 2003; 198(3): 433 - 442. [Abstract] [Full Text] [PDF]
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N. Meissner, J. Radke, J. F. Hedges, M. White, M. Behnke, S. Bertolino, M. Abrahamsen, and M. A. Jutila Serial Analysis of Gene Expression in Circulating {gamma}{delta} T Cell Subsets Defines Distinct Immunoregulatory Phenotypes and Unexpected Gene Expression Profiles J. Immunol., January 1, 2003; 170(1): 356 - 364. [Abstract] [Full Text] [PDF]
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E. Wilson, J. F. Hedges, E. C. Butcher, M. Briskin, and M. A. Jutila Bovine {gamma}{delta} T Cell Subsets Express Distinct Patterns of Chemokine Responsiveness and Adhesion Molecules: A Mechanism for Tissue-Specific {gamma}{delta} T Cell Subset Accumulation J. Immunol., November 1, 2002; 169(9): 4970 - 4975. [Abstract] [Full Text] [PDF]
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S. A. Huber, D. Sartini, and M. Exley V{gamma}4+ T Cells Promote Autoimmune CD8+ Cytolytic T-Lymphocyte Activation in Coxsackievirus B3-Induced Myocarditis in Mice: Role for CD4+ Th1 Cells J. Virol., October 2, 2002; 76(21): 10785 - 10790. [Abstract] [Full Text] [PDF]
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 M. Lahn, A. Kanehiro, K. Takeda, J. Terry, Y.-S. Hahn, M. K. Aydintug, A. Konowal, K. Ikuta, R. L. O'Brien, E. W. Gelfand, et al. MHC class I-dependent Vgamma 4+ pulmonary T cells regulate alpha beta T cell-independent airway responsiveness PNAS, June 25, 2002; 99(13): 8850 - 8855. [Abstract] [Full Text] [PDF]
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S. Huber, C. Shi, and R. C. Budd {gamma}{delta} T Cells Promote a Th1 Response during Coxsackievirus B3 Infection In Vivo: Role of Fas and Fas Ligand J. Virol., June 5, 2002; 76(13): 6487 - 6494. [Abstract] [Full Text] [PDF]
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 I Bank, L Cohen, M Mouallem, Z Farfel, E Grossman, and A Ben-Nun {gamma}{delta} T cell subsets in patients with arthritis and chronic neutropenia Ann Rheum Dis, May 1, 2002; 61(5): 438 - 443. [Abstract] [Full Text] [PDF]
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 M. J. Skeen, E. P. Rix, M. M. Freeman, and H. K. Ziegler Exaggerated Proinflammatory and Th1 Responses in the Absence of gamma /delta T Cells after Infection with Listeria monocytogenes Infect. Immun., December 1, 2001; 69(12): 7213 - 7223. [Abstract] [Full Text] [PDF]
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 B.B. Moore, T.A. Moore, and G.B. Toews Role of T- and B-;lymphocytes in pulmonary host defences Eur. Respir. J., November 1, 2001; 18(5): 846 - 856. [Abstract] [Full Text] [PDF]
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S. A. Huber, D. Graveline, W. K. Born, and R. L. O'Brien Cytokine Production by V{gamma}+-T-Cell Subsets Is an Important Factor Determining CD4+-Th-Cell Phenotype and Susceptibility of BALB/c Mice to Coxsackievirus B3-Induced Myocarditis J. Virol., July 1, 2001; 75(13): 5860 - 5869. [Abstract] [Full Text] [PDF]
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 M. W. Cunningham Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis Am. J. Pathol., July 1, 2001; 159(1): 5 - 12. [Full Text] [PDF]
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B. Altincicek, J. Moll, N. Campos, G. Foerster, E. Beck, J.-F. Hoeffler, C. Grosdemange-Billiard, M. Rodriguez-Concepcion, M. Rohmer, A. Boronat, et al. Cutting Edge: Human {{gamma}}{{delta}} T Cells Are Activated by Intermediates of the 2-C-methyl-D-erythritol 4-phosphate Pathway of Isoprenoid Biosynthesis J. Immunol., March 15, 2001; 166(6): 3655 - 3658. [Abstract] [Full Text] [PDF]
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M. Girardi, J. Lewis, E. Glusac, R. B. Filler, L. Geng, A. C. Hayday, and R. E. Tigelaar Resident Skin-specific {gamma}{delta} T Cells Provide Local, Nonredundant Regulation of Cutaneous Inflammation J. Exp. Med., April 1, 2002; 195(7): 855 - 867. [Abstract] [Full Text] [PDF]
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