| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Dental Branch, Department of Basic Sciences, University of Texas Health Science Center, Houston, TX 77030
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
synthesis. Unlike CD8+ lymph node
cells, IELs express high levels of the FasL gene, but do not express
surface FasL until after CD3-mediated stimulation has occurred.
Additionally, anti-CD3 stimulation of IELs in the presence of
actinomycin-D did not inhibit FasL expression, suggesting that
regulation FasL expression on IELs is controlled at least partially at
the posttranscriptional level. Following CD3-mediated stimulation, IELs
synthesize and secrete IFN- more rapidly and to greater levels than
CD8+ lymph node cells, and they acquire the phenotype of
fully activated effector cells as seen by an up-regulation of CD44,
Ly-6C, OX40, FasL, and CD25 with the kinetics of memory T cells, with
down-regulation of CD45RB expression. These findings indicate that
contrary to previous interpretations, most small intestine IELs are not
fully activated T cells, but rather that they are semiactivated T cells
ready to shift to a fully activated state once a CD3-mediated signal
has been received. These data also imply that under appropriate
conditions it is possible for T cells to be sustained in a state of
partial activation. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and/or 
IELs revealed the striking yet
paradoxical finding of constitutive expression of genes of activated
cytotoxic T cells (granzyme A, granzyme B, and the cytotoxic-associated
proteins serglycin, Fas ligand (FasL), and cryptidin) while
concomitantly expressing genes involved in immune down-regulation,
including CTLA-4, Ly-49E-G, the NK receptor gp49B, and PD-1/programmed
cell death 1 genes (1, 2).
Similarly, an important unresolved question is whether IELs are
activated naive effector cells or whether they are memory
CD8+ T cells poised for reactivation. Studies
using transgenic mice expressing TCR for an OVA peptide (OT-1 mice)
indicate that T cells can be activated in situ in the gut epithelium,
and that cytotoxic activity to nominal Ags increases with immunization
(3). Moreover, naive and memory CD8+
T cells can migrate to or be recruited into the intestinal epithelium
(3, 4). However, because nearly all T cells in those
experimental systems consist of TCR cells, a subset that makes up
only about half of the total IELs (see Results),
those studies provide little information about the other types of T
cells present among the IELs, including populations that originate from
precursors within the intestinal mucosa and may not recirculate
(5). Additionally, if in fact most IELs are memory T
cells, it is hard to reconcile why IELs from OT-1 mice not primed with
OVA are cytotoxic ex vivo (3) unless some type of regional
preactivation event has occurred in vivo. In an effort to resolve those
differences, murine IELs were studied using freshly isolated cell
preparations with a panel of markers associated with T cell activation
and/or memory, and by following functional and phenotypic changes that
occur shortly after CD3-mediated stimulation. Our findings indicate
that most CD8+ IELs are partially activated T
cells that are phenotypically similar to naive T cells yet can proceed
into a state of full activation with the kinetics of memory cells.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Adult female BALB/c 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.
Cell isolation, purification, and culture
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 reagents; 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-ml syringe barrels containing wetted nylon wool, centrifuged, suspended in 3 ml of 40% isotonic Percoll, layered on top of 70% isotonic Percoll, and centrifuged for 20 min at 600 x g. IELs were recovered from the Percoll interface. Lymph node cells (LNCs) were isolated by pressing lymph node tissues through a 60-mesh stainless steel screen into supplemented RPMI 1640 for autoMACS cell sorting.
Purification of CD8+ IELs and LNCs by MACS was
done using an autoMACS cell sorter (Miltenyi Biotec, Auburn, CA). For
IELs, 15–20 x 106 freshly isolated IELs
were reacted with 1 ml of anti-CD16 tissue culture supernatant for
10 min at 4°C. Cells were centrifuged and washed with labeling buffer
(PBS (pH 7.2) supplemented with 2 mM EDTA) and reacted with 1 ml of
unlabeled anti-CD4 mAb plus 1 ml of unlabeled G8.8 mAb
(6) for 20 min at 4°C. G8.8 mAb was used to deplete
epithelial cells from IEL preparations as previously described
(7). Our studies using G8.8 indicate that only 
3% of
the total IELs express the G8.8 Ag, and that isolation of IELs using
this technique yields highly pure preparations (95–97% IELs) based on
expression of the leukocyte-common Ag (7). Cells were
washed with labeling buffer and reacted with 20 µl of anti-rat
microbeads (Miltenyi Biotec) in 180 µl of labeling buffer for 15 min
at 4°C. Cells were washed, suspended in 1 ml of separation buffer
(PBS (pH 7.2) supplemented with 2 mM EDTA plus 0.5% BSA), and applied
to autoMACS. For CD8+ LNC enrichment, autoMACS
sorting was done using 15–20 x 106 cells
reacted with anti-B220 and anti-CD4 mAbs, followed by treatment
with anti-rat microbeads to remove B cells and
CD4+ T cells similar to that described for IELs.
Flow cytometric cell sorting of CD8+ IELs was
done at the Baylor College of Medicine Department of Immunology flow
cytometry core facility (Houston, TX) using an EPICS cell sorter
(Coulter Scientific, Hialeah, FL).
Microtiter plates (24- or 96-well) were coated overnight with 10
µg/ml of anti-hamster mAb in PBS. Wells were washed with PBS and
reacted with 5 µg/ml of hamster anti-mouse CD3 or control hamster
mAb. IELs or LNCs were cultured in coated 24-well plates at a density
of 1.0–2.0 x 106 cells/2 ml, or in coated
96-well plates at a density of 5 x 105
cells/ml in 200 µl in supplemented RPMI 1640 (Cell isolation,
purification, and culture) containing 4 ng/ml rIL-2 and 100
ng/ml rIL-15 (Sigma-Aldrich). Cells were collected after 24 h,
stained, and analyzed by flow cytometry, or cell-free supernatants were
collected at the designated intervals for IFN- assays. Actinomycin-D
(Sigma-Aldrich) was used at 2 µg/ml, a concentration previously
reported to inhibit transcription in T cells (8).
Antibodies
Abs used were: purified NA/LE anti-CD3 (145-2C11),
FITC-anti-CD8 (53-6.7), PE-CD8 (53-5.8), FITC-anti-TCR
(H57), FITC-anti-TCR (GL3), biotin-anti-CD45RB (16A),
CyChrome anti-CD44 (IM7), PE-anti-CD25 (PC61), PE-anti-CD69
(H1.2F3), biotin-anti-OX40 (OX86), biotin-anti-Ly-6C (AL-21),
biotin-anti-FasL (MFL-3), FITC-, PE-, and Cy-isotype control Abs,
purified anti-hamster Ig (G94-56), purified hamster IgG, propidium
iodide, streptavidin-CyChrome, anti-CD16/32 Fc block (2.4G2; all
reagents; BD PharMingen, San Diego, CA). Anti-CD4 (GK1.5) and
anti-B220 (RA3-6B2) cells were purchased from American Type Culture
Collection (Manassas, VA). G8.8 cells were generously provided by Dr.
A. Farr (University of Washington, Seattle, WA). 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, Mountain View, CA). In two color histograms,
background staining by species-matched control reagents is demarcated
by the position of cells in the lower left quadrant.
Immunocytochemistry
Immunocytochemistry was done using small intestine tissues frozen in liquid N2. Acetone-fixed 5-µM sections were treated for 15 min at room temperature with avidin block (DAKO, Carpinteria, CA), washed, and treated for 15 min at room temperature with biotin block (DAKO). Tissues were washed and treated for 15 min at room temperature with anti-CD16/32 (BD PharMingen). Tissues were washed and reacted with PE-anti-CD69 for 3 h at 4°C. Tissues were washed and examined with an Olympus BH-2 immunofluorescence microscope (Olympus, Lake Success, NY).
RT-PCR analyses
CD8+ IELs and LNCs were enriched by
autoMACS cell sorting. RNAs were extracted from 1000 cells from
each group using an RNAqueous-4PCR kit (Ambion, Austin, TX). A total of
0.5 µg of RNAs were converted to cDNAs with an Advantage RT-for-PCR
kit (Clontech Laboratories, Palo Alto, CA). PCR amplification was done
using the following primers: FasL forward 5'-CAGCTCTTCCACCTGCAGAAGG-3',
FasL reverse 5'-AGATTCCTCAAAATTGATCAGGAGAG-3'; actin forward
5'-ATGGATGACGATATCGCTG-3', actin reverse
5'-ATGAGGTAGTCTGTCAGGT-3' (Invitrogen, Carlsbad, CA). Semiquantitative
RT-PCR was done by adding 3-fold serially diluted cDNAs from LNC or IEL
FasL or -actin to tubes with PCR buffers (Applied Biosystems, Foster
City, CA) and Taq polymerase (Promega, Madison, WI).
Amplification of FasL consisted of 35 cycles at
95oC for 1 min, 55oC for 2
min, 72oC for 3 min; for actin consisted of 30
cycles at 95oC for 1 min,
50oC for 1 min, and 72oC
for 1 min using a Biometra T-Gradient thermocycler (Whatman Biometra,
Gottingen, Germany).
Enzyme-linked immunoassay and redirected cytotoxicity assay
Cell-free supernatants were collected from IEL and LNC cultures
and frozen at -70°C. Samples were analyzed together to reduce
variation between assays. Secreted IFN- was measured with a
commercial cytokine assay kit (eBioscience, San Diego, CA)
using the manufacturer’s protocols and standards. Redirected
cytotoxicity assays were done as previously reported
(9).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Consistent with other reports (9, 10), murine IELs
were primarily CD8+ T cells of which most were
CD8 cells (Fig. 1
A) that
consist of TCR (Fig. 1B) or TCR cells (Fig. 1C). Nearly all CD8+ IELs expressed
CD69 ex vivo (Fig. 1D) and in situ (Fig. 1E), and
had lytic activity when tested in redirected cytotoxicity assays (Fig. 1F), thus demonstrating a classic functional property of
activated CTL.
|
A), a marker expressed on
activated CD8 T cells (11) and on IELs after anti-CD3
stimulation (9). Moreover, only a small proportion of
CD8+ IELs expressed Ly-6C (Fig. 2B),
FasL (Fig. 2C), or CD25 (Fig. 2D), all of which
have been linked to activated peripheral CTL (12, 13, 14, 15).
CD8+ IELs were CD45RBhigh
(Fig. 2E) and CD44low/int (Fig. 2F). Because memory T cells express low levels of CD45RB
(16), high levels of CD44 (17) and Ly-6C
(18), and are low-to-negative for CD69 expression
(18), this is not a phenotype compatible with a population
of memory T cells. Conversely, because IELs express some properties of
activated naive T cells, although they lack other distinguishing
features of fully activated T cells such as OX40 and CD25 expression
and high levels of FasL expression, IELs cannot be readily defined as
either naive or memory T cells using conventional standards. It should
be noted that because down-regulation of CD62 ligand is needed
for homing of lymphocytes and lymphocyte precursors to mucosal tissues
(3), the level of CD62 ligand expression on IELs is not a
reliable marker of memory T cells in the intestine.
|
but rapidly up-regulate
IFN- synthesis in a manner typical of memory T cells following CD3
triggering
To more precisely define the activational state of CD8 IELs,
IFN- synthesis was studied for CD8+ IELs. This
was selected because IFN- is produced by activated but not resting
CD8+ T cells (19), and is secreted
more rapidly by memory T cells than naive T cells upon immune
stimulation (20). Based on intracellular IFN- staining,
CD8+ IELs did not synthesize IFN- (Fig. 3, A and B) even
though those cells were cytotoxic and expressed CD69 (Fig. 1
, D and F).
|
. Several new findings emerged from these
experiments. First, following anti-CD3 stimulation, IELs consisted
of a CD8high population (Fig. 3C, R4)
typical of freshly isolated IELs (Fig. 3A), and a population
of CD8low cells (Fig. 3C, R3) that was
not present in freshly isolated IELs (Fig. 3A). Within both
of those groups, approximately half of all cells expressed
intracellular IFN- after short-term anti-CD3 stimulation (Fig. 3, E and F), implying that those IELs had rapidly
proceeded to a state of full activation. Second, after 18 h of
anti-CD3 stimulation under conditions identical with IELs, LNCs
retained the basic LNC CD8 phenotype consisting of
CD8high cells (Fig. 3G, R4), and did
not express significant levels of intracellular IFN- (Fig. 3, H–J). Interestingly, when an equivalent number of
MACS-purified CD8+ IELs and LNCs were analyzed
for expression of the FasL gene, IELs expressed 9-fold higher levels
of FasL gene compared with LNCs (Fig. 4),
yet they expressed minimal surface FasL (see Fig. 2C).
Moreover, when IELs were cultured for 24 h with immobilized
anti-CD3 mAb, with or without 2 µg/ml actinomycin-D, an
equivalent proportion of cells in both groups expressed surface FasL
(Fig. 5). Taken together, these findings
indicate that the expression of FasL on IELs is regulated
posttranscriptionally, and they support the notion that resident IELs
are partially activated non-memory T cells.
|
|
was further
demonstrated using equivalent numbers of MACS-purified
CD8+ IELs and LNCs cultured in microplates coated
with anti-CD3 or control mAbs. Supernatants were collected from
individual wells at intervals poststimulation and assayed for secreted
IFN- by enzyme-linked immunoassay. Shown in Fig. 6, throughout the time of analyses the
kinetics of IFN- production differed significantly between IELs and
LNCs in that CD8+ IELs produced significantly
higher levels of IFN- sooner than that of an equivalent number of
LNCs under the same stimulatory conditions. Without stimulation,
IFN- production was negligible (<25 pg/ml) for both IELs and
LNCs.
|
Finally, to identify the changes in activation and memory
phenotypic markers on IELs after short-term CD3-mediated activation,
CD8+ IELs purified by flow cytometric cell
sorting were cultured for 24 h with or without anti-CD3
stimulation. Cells were collected and stained for expression of CD44,
CD45RB, Ly-6C, OX40, and FasL using propidium iodide to discriminate
dead and viable cells. In the absence of anti-CD3 stimulation,
little change occurred in the expression of CD44, CD45RB, Ly-6C, OX40,
or FasL, (Fig. 7, control Ab) compared
with freshly isolated IELs (Figs. 1 and 2). However, of particular
interest was the dramatic change in the expression of all five markers
as a consequence of CD3-mediated stimulation (Fig. 7, anti-CD3 Ab).
This included an up-regulation of Ly-6C, OX40, and FasL expression,
high level of expression of CD44, and a decrease in CD45RB
expression.
|
) in a manner similar to that
which occurs for memory T cells (18). Changes in CD25
expression did not occur in 24-h IEL cultures in the presence of
control Ab stimulation (data not shown). These findings, coupled with
the studies of IFN- synthesis by fresh IELs, strongly suggest that
although IELs bear many phenotypic properties of non-memory T cells,
CD3-mediated signaling leads to activation in a manner kinetically
typical of memory T cells.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
synthesis) by IELs
that have not received a CD3-mediated signal is curious. However,
clearly IELs can be induced to secrete IFN- as reported in this
study and as seen in studies of mice infected orally with reovirus in
which there was an increase in IFN- message in IELs following
infection (23). Similarly, IFN- mRNA and secreted
IFN- have been reported for IELs following oral Listeria
monocytogenes infection (24). IFN-
production by IELs also is increased in mice following injection of
nonlethal doses of LPS (25), and synthesis of IFN- by
IELs may be influenced at least in part by intestinal-derived
cytokines, possibly stem cell factor (26) and IL-15
(27). Moreover, because IFN- synthesis has been linked
to tissue destruction of intestinal epithelial cells as seen in an
IL-12 model of inflammatory bowel disease (28), under
normal conditions IFN- may have a protective role in the removal of
diseased or infected epithelial cells, although continual synthesis of
IFN- by fully activated IELs could have severe biological
consequences if left unchecked. However, IFN- also may be involved
in oral tolerance (29, 30), suggesting a complex role for
IFN- at the level of the intestinal mucosa. In that vein also, our
observation that the FasL gene is expressed in IELs even though only
low levels of surface FasL protein are present, and the ability of IELs
to express FasL when stimulated in the presence of concentrations of
actinomycin-D that inhibit T cell transcription in other studies
(8) suggest that FasL protein expression on IELs is
controlled through posttranscriptional mechanisms. Therefore,
this would provide a rapid mechanism for further
up-regulating the lytic activity of IELs along with IFN-
synthesis. In short, the ability to dissociate cytolytic activity from
IFN- activity in the partially activated state would permit rapid
full activation of IELs after cognate Ag recognition and CD3 signaling
have occurred. Taken together, these findings indicate that the process of T cell activation in the gut epithelium (and possibly elsewhere) is not a cascade of activational steps, one automatically following the other until full activation has taken place, but rather that multiple consequential signals are needed to drive the activational process to completion. Furthermore, it appears that this process can be suspended and then resumed after the initial activation signal has been initiated. In that context, it will be of interest to determine whether some T cells in extraintestinal peripheral lymphoid tissues also exist as partially activated cells. Interestingly, some evidence for this comes from studies that have identified a population of peripheral "resting primed" CD8+ T cells in lymphocytic choriomeningitis virus-infected mice that have properties similar to those reported in this study, with a potential for hyperresponsive Ag-induced activation (31). Questions that remain to be addressed center on the types of signals that prompt the first stage of IEL activation, as well as mechanisms that halt the activational process in the semiactivated state. Both issues are central to an understanding of how IELs respond to foreign Ag, and will be needed to elucidate mechanisms that prevent broad-spectrum tissue destruction by IELs as occurs in situations of chronic intestinal inflammation and immunopathology. The findings described in this study should enable further exploration into those areas by more accurately defining the stages of IEL activation.
Finally, the differences between CD8+ IELs and
CD8+ T cells in extraintestinal lymphoid
compartments are notable in many ways, in part due to the high degree
of heterogeneity of murine IELs (32), and the potential
for some IELs to develop along an extrathymic, intraintestinal pathway
(5). Moreover, recent studies have linked the recognition
of MHC class I thymus leukemia Ag to CD8+
IELs, and have demonstrated that those interactions are involved in the
homeostatic maintenance of the intestinal epithelium by IELs
(33). A dynamic role for IELs, both in terms of a
classical immune defense response and for the elimination of damaged or
senescent epithelial cells, may require rapidly generated effector
activity similar to that described in this study. Experiments are
underway to explore the events involved in IEL activation in the
context of both health and disease at the level of the intestinal
epithelium.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. John R. Klein, Dental Branch, Department of Basic Sciences, University of Texas Health Science Center, Suite 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; FasL, Fas ligand; LNC, lymph node cell; int, intermediate.
Received for publication June 28, 2002. Accepted for publication August 27, 2002.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
intraepithelial lymphocytes as suggested by their transcription profile. Proc. Natl. Acad. Sci. USA 98:10261.+ and TCR+ intraepithelial lymphocytes provided by serial analyses of gene expression (SAGE). Immunity 15:419.[Medline]
, and IL-10 regulation. J. Immunol. 167:6717. synthesis by mouse CD8+ T cells correlates with shifts in the frequency of cell subsets defined by membrane CD44, CD45RB, 3G11, and MEL-14 expression. J. Immunol. 151:575.[Abstract]
+ intestinal intraepithelial lymphocytes. J. Immunol. 162:1896.+ intestinal intraepithelial lymphocytes. J. Immunol. 163:5843., TNF) in the induction of epithelial cell death and renewal. Eur. J. Immunol. 28:730.[Medline]
signaling pathway. J. Immunol. 163:4728. induction during oral tolerance reduces T-cell migration to sites of inflammation. Gastroenterology 119:129.[Medline]
and the nonclassical MHC class I molecule, TL. Science 294:1936.This article has been cited by other articles:
|
|
 |
|
  M. Beyer, J. Karbach, M. R. Mallmann, T. Zander, D. Eggle, S. Classen, S. Debey-Pascher, M. Famulok, E. Jager, and J. L. Schultze Cancer Vaccine Enhanced, Non-Tumor-Reactive CD8+ T Cells Exhibit a Distinct Molecular Program Associated with "Division Arrest Anergy" Cancer Res., May 15, 2009; 69(10): 4346 - 4354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Terabe, Y. Tagaya, Q. Zhu, L. Granger, M. Roederer, T. A. Waldmann, and J. A. Berzofsky IL-15 Expands Unconventional CD8{alpha}{alpha}NK1.1+ T Cells but Not V{alpha}14J{alpha}18+ NKT Cells J. Immunol., June 1, 2008; 180(11): 7276 - 7286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Montufar-Solis, H.-C. Wang, and J. R. Klein Stimulatory and costimulatory effects of IL-18 directed to different small intestinal CD43 T cell subsets J. Leukoc. Biol., November 1, 2007; 82(5): 1166 - 1173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Critchfield, D. Lemongello, D. H. Walker, J. C. Garcia, D. M. Asmuth, R. B. Pollard, and B. L. Shacklett Multifunctional Human Immunodeficiency Virus (HIV) Gag-Specific CD8+ T-Cell Responses in Rectal Mucosa and Peripheral Blood Mononuclear Cells during Chronic HIV Type 1 Infection J. Virol., June 1, 2007; 81(11): 5460 - 5471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Liu, D. P. Evanoff, X. Chen, and Y. Luo Urinary Bladder Epithelium Antigen Induces CD8+ T Cell Tolerance, Activation, and Autoimmune Response J. Immunol., January 1, 2007; 178(1): 539 - 546. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Leav, M. Yoshida, K. Rogers, S. Cohen, N. Godiwala, R. S. Blumberg, and H. Ward An Early Intestinal Mucosal Source of Gamma Interferon Is Associated with Resistance to and Control of Cryptosporidium parvum Infection in Mice Infect. Immun., December 1, 2005; 73(12): 8425 - 8428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
B. L. Shacklett, C. A. Cox, M. F. Quigley, C. Kreis, N. H. Stollman, M. A. Jacobson, J. Andersson, J. K. Sandberg, and D. F. Nixon Abundant Expression of Granzyme A, but Not Perforin, in Granules of CD8+ T Cells in GALT: Implications for Immune Control of HIV-1 Infection J. Immunol., July 1, 2004; 173(1): 641 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Klein and H.-C. Wang Characterization of a novel set of resident intrathyroidal bone marrow-derived hematopoietic cells: potential for immune-endocrine interactions in thyroid homeostasis J. Exp. Biol., January 1, 2004; 207(1): 55 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Shacklett, C. A. Cox, J. K. Sandberg, N. H. Stollman, M. A. Jacobson, and D. F. Nixon Trafficking of Human Immunodeficiency Virus Type 1-Specific CD8+ T Cells to Gut-Associated Lymphoid Tissue during Chronic Infection J. Virol., May 15, 2003; 77(10): 5621 - 5631. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
