| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
CUTTING EDGE |
*
Laboratory of Immunology and Vascular Biology, Department of Pathology, and the Digestive Disease Center, Department of Medicine, Stanford University Medical School, Stanford, CA, 94305; and
Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
(SDF-1), a widely
expressed chemokine to which most mononuclear leukocytes respond
(5, 13). |
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
Thymi (from which nonthymic tissue was carefully removed) were obtained from 5- to 7-wk-old mice. The organs were gently disrupted between the frosted ends of two glass slides and passed through nylon mesh to remove aggregates. The thymocytes were incubated 2 x 30 min in RPMI 1640 medium with 10% bovine serum in a T-175 flask (Nunc, Naperville, IL) to remove adherent cells. Lymph node lymphocytes were obtained as described (5).
Chemotaxis assays
Migration assays were conducted as described (5):
5 x 105 cells were added to the upper wells
of 5-µm pore, polycarbonate 24-well tissue culture inserts (Costar,
Cambridge, MA) in 100 µl, with 600 µl of chemokine dilution (or
medium) in the bottom well. Four chemotactic wells were set up for each
chemokine, and 16 wells for the medium control. All migrations were
conducted in RPMI 1640 with 10% bovine serum at 37°C in 8%
CO2 for 90 min. Chemokines used were recombinant
mouse (rmu) TECK, SLC, MIP-3ß, and MDC (R&D Systems, Minneapolis, MN)
and synthetic human SDF-1 (which has been shown to attract mouse
lymphocytes (5); Gryphon Sciences, South San Francisco,
CA). Optimal chemotactic concentrations were determined as described
(5), and these concentrations were used for each
experiment: recombinant human SDF-1, 100 nM; rmuTECK, 1 µM;
rmuSLC, 100 nM; rmuMIP-3ß, 100 nM; and rmuMDC, 100 nM. A 100-µl
aliquot of migrated cells recovered from each well was counted using
comparison to a known number of beads as an internal standard, as
described (5, 14). The remainder of the cells were stained
with directly conjugated mAbs (see below). The number of cells in the
starting population and the migrated population was calculated for each
phenotype, and the percent migration was determined from these
values.
Flow cytometry
The migrated cells and starting populations were stained for
flow cytometry with one of three different four-color mAb (and/or
lectin) combinations: anti-CD4-FITC (clone RM4–5; PharMingen, San
Diego, CA), anti-CD8-PE (clone 53–6.7; PharMingen),
anti-TCRß-biotin (clone H57–597; PharMingen), or
anti-CD69-biotin (clone H1.2F3, Pharmingen) and
anti-L-selectin/CD62L-APC (clone MEL-14; a generous gift of the
Herzenberg lab, Stanford University); or peanut agglutinin (PNA)-FITC
(EY Laboratories, San Mateo, CA), anti-CD24a/heat stable Ag-PE
(clone M1/69; PharMingen), anti-CD3
-biotin, and
anti-L-selectin/CD62L-APC. All protocols were followed by
cychrome-streptavidin (PharMingen). Flow cytometry was performed on a
FACScalibur driven by CellQuest software (Becton Dickinson, Mountain
View, CA).
Semiquantitative RT-PCR
Total RNA was isolated from 50,000 sorted cells by a modification of the single-step acid-guanidinium-phenol-chloroform method as described (15). Sorted populations were >96% pure. After treatment with RNase-free DNase, the total RNA was divided into two equal parts: one part was reverse transcribed into cDNA and the other was mock transcribed. Then, 2 µl of the reaction mixtures were used for PCR using 50 pmol of sense and antisense primers according to the manufacturer’s protocol (Life Technologies, Rockville, MD). Amplification was performed for 15, 20, 25, 30, or 35 cycles as follows: 1 min at 94°C, 2 min at 50°C, and 1.5 min at 72°C. PCR products were separated on a 2% agarose gel, transferred onto a Hybond membrane, probed with a 32P 5'-end-labeled internal oligonucleotide, and analyzed by phosphoimagery. Normalization of the bands was conducted by phosphoimagery at a number of cycles that was exponential for each gene. No specific PCR products were detected when the corresponding mock-transcribed mixture was used as template. The PCR primers for murine CCR7 were: 5'-CCA GGA AAA ACG TGC TGG TG-3' and 5'-GGC CAG GTT GAG CAG GTA GG-3'; the primers for CCR4 were: 5'-CCA GGC TAC AGA AAC CCT GG-3' and 5'-TGT GTG GAG CTT GTT AAC GC-3'. The probes for CCR7 and CCR4 were 5'-GAC TAC ATC GGC GAG AAT ACC ACG GTG GAC-3' and CTC TTA CAC GCA GTC CAC TGT GGA TC-3', respectively.
|
Results and Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
A). Each chemokine was used
near the optimal concentration, defined as the concentration giving the
maximal thymocyte migration into the lower chamber (not shown).
Checkerboard analysis (a series of chemotaxis experiments in which a
given concentration of agonist is placed in the upper, lower, neither,
or both chambers to distinguish direction-dependent chemotaxis from
ligand-induced random motion) confirmed that all responses were
chemotactic with little chemokinetic component (not shown). Thymocytes
responded well to TECK (4), but peripheral T cells, as a
bulk population, responded poorly. Conversely, peripheral T cells
migrated much more efficiently than thymocytes to the CCR7 ligands SLC
and MIP-3ß, although the thymocyte response to these chemokines was
also well above background (11). Thymocytes migrated
poorly but significantly to MDC, whereas lymph node cells from these
young mice did not respond detectably to MDC.
|
B). Cortical
thymocytes responded best to TECK and SDF-1, but did not respond
appreciably to MDC, MIP-3ß, or SLC. In contrast, medullary thymocytes
responded dramatically well to MIP-3ß and SLC and, to a lesser
extent, to SDF-1, TECK, and MDC.
To understand in more detail how responsiveness to chemokines is
modulated during thymic development, migratory responses were analyzed
independently for five well-established phenotypically defined stages
of the lineage leading to CD4(+) T cells, as follows: 1) CD4/CD8 DP,
TCRß- (early cortical); 2) CD4/8 DP,
TCRßlow (late cortical); 3) CD4/8 DP,
CD69+ (postpositive selection, transitional
between medulla and cortex (16, 17, 18, 19); 4) CD4 SP,
CD69+, L-selectinlow/-
(19); and 5) CD4 SP, CD69-,
L-selectinhigh (19). In Fig. 2, each panel shows the responsiveness to
a given chemokine of cells belonging to each of these five
developmental stages.
|
(upper
left) attracted cells of each phenotype similarly. SLC and
MIP-3ß (middle panels), which act through their common
receptor CCR7, failed to attract either of the cortical phenotypes but
yielded significant chemotaxis of transitional cells. Responsiveness of
thymocytes to these chemokines increased throughout the
sequential medullary stages. The TECK pattern (bottom left) was nearly reciprocal to those of the CCR7 ligands: cortical, transitional, and early medullary stages responded equally well to TECK, but all responsiveness was lost in the most mature medullary phenotype.
MDC responsiveness (bottom right) appeared in a pattern dramatically different from the others. The earliest and latest stages of cells did not respond to MDC; responses only occurred during a brief period of CD4 thymic development comprising the transitional and early medullary stages.
Fig. 3 shows the expression of developmental markers on the subset of
CD4 SP medullary thymocytes responding to each of the chemokines
tested. Unmanipulated CD4 SP medullary thymocytes displayed an early
medullary to late medullary ratio of 
55:35. CD4 SP medullary
thymocytes attracted to SDF-1, SLC, and MIP-3ß maintained similar
ratios. In contrast, late medullary cells were largely absent from the
populations attracted to TECK and MDC.
|
ß- early cortical cells
(stage 1 in Fig. 2) were chosen as a
representative population not responsive to these chemokines, and CD4
SP, CD69+ early medullary cells (stage 4 in Fig. 2) were
chosen as representative responders. CCR4 and CCR7 mRNA was nearly
undetectable in the early cortical population (see Fig. 4). The later CD4/8 DP,
TCRßlo cortical population was also negative
for both of these mRNAs (not shown). In contrast, CCR4 and CCR7 mRNAs
were expressed at high levels in the medullary cells. Expression of a
housekeeping gene (G3PDH) indicates equal loading of the wells. Thus,
the appearance of CCR4 and CCR7 mRNA correlates with the appearance of
functional responsiveness to their chemokine ligands during thymic
development.
|
and 3) and expression of
CCR7 mRNA (Fig. 4) appear well before the stage of final exit from the
thymus and thus are not likely to trigger escape from the thymus.
However, the appearance of responsiveness to CCR7 ligands in
transitional (stage 3) thymocytes suggests a potential role in the
migration of positively selected thymocytes from the cortex to the
medulla. Alternatively, as CCR7 is important for homing of naive T
cells to peripheral lymphoid organs (5, 7),4,5 increased responsiveness to CCR7
during the latter stages of thymic development may indicate an
increasing readiness to home to such peripheral sites, as seen for
L-selectin expression (19, 22).
After entry into the medulla, SP thymocytes are thought to undergo
a process of negative selection. The small proportion of medullary
thymocytes that survive are released into the periphery within a few
days (1). During their residence in the medulla (as
mentioned above), these thymocytes lose expression of CD69 and gain
expression of peripheral homing molecules such as L-selectin (CD62L)
before emigrating from the thymus as naive T cells (19, 22). The inability of naive lymph node T cells to migrate to
TECK (Fig. 3, inset) contrasted with the TECK responsiveness
of the bulk of both cortical and medullary thymocytes (Fig. 1B) and suggested that loss of TECK activity might occur
late during the process of T cell maturation.
Consistent with this hypothesis, we found that the response of
medullary thymocytes to TECK was inversely related to their expression
of L-selectin and positively correlated to CD69 expression: as
illustrated for CD4 SP thymocytes in Fig. 3 (lower
right),
CD69+/L-selectinhigh cells
are dramatically underrepresented among cells migrating to TECK,
whereas they are slightly enriched among cells recruited to SLC and
MIP-3ß. We conclude that loss of responsiveness to TECK occurs at the
latest identifiable stage in thymocyte maturation—just before
emigration to the periphery. Naive peripheral CD4 T cells display no
appreciable response to TECK (Fig. 2, inset), implying that
its expression during the development of these cells is devoted to a
thymic role, perhaps as a thymic retention factor (see below).
The regulation of MDC responsiveness shares features with those of both TECK and the CCR7 ligands. As for SLC and MIP-3ß, MDC responsiveness first appears in the CD4/8 DP/CD69(+) stage, implying a potential role (along with SLC and MIP-3ß) in migration of positively selected thymocytes from the cortex to the medulla. As for TECK, responsiveness to MDC disappears at the latest stage of thymic development (stage 5, just before release), implying a potential role for MDC as a thymic retention factor. Moreover, as for TECK, naive peripheral cells displayed no appreciable response to MDC.
The abrupt transitions revealed here may be representative of broader developmental switches, during which responses to multiple chemokines may be coordinately reprogrammed to redirect the microenvironmental homing of T cells. Altered chemokine responses may also regulate other aspects of T cell behavior. Although it is as yet not feasible to determine accurately the local gradients and/or patterns of presentation of secreted chemokines within tissues in vivo, immunohistologic studies suggest that SLC (TCA-4) and CCR4 ligands are abundant in the thymic medulla (23). Thus, they may be well positioned to provide a signal for recruitment of maturing, newly SLC-responsive thymocytes from the cortex. Conversely, our data do not support the hypothesis that TECK mediates cortex medulla migration. Instead, to the extent that its role is to regulate cell positioning, TECK may be involved in precursor recruitment into the thymus, and/or may help retain cells in the thymus until responsiveness is lost in association with up-regulation of peripheral homing receptors. An inverse gradient of TECK between the thymus and blood (or lymph) might help prevent emigration before terminal maturation.
Although most thymocytes were responsive to SDF-1, and SDF-1 is
highly expressed in the thymus, there was no appreciable change in
SDF-1 responsiveness during development. Therefore, a potential role
for this chemokine in targeted migratory events during thymic
development is not apparent. The role of SDF-1 in peripheral homing
of mature lymphocytes to specific sites is similarly hard to
understand, as it is apparently expressed ubiquitously and its receptor
(CXCR4) is found on almost all mononuclear cells. Indeed,
CXCR4- lymphocytes develop and seed peripheral
lymphoid tissues normally (24). Of note, Suzuki et al.
(25) reported more intense cortical than medullary CXCR4
expression by in situ hybridization and concluded that SDF responses
might be lost during the cortical to medullary transition. Our data
reveal that, at the functional level, this is not true. Moreover, in
the human system, thymocyte CXCR4 expression (as assessed by flow
cytometry using two independently derived mAbs) remains constant
throughout thymic development (J.J.C., manuscript in preparation).
Therefore, it is likely that the higher intensity of hybridization in
the cortex reflects simply the much greater density of lymphocytes per
unit area residing there (1).
The rapid switch of chemokine response patterns may prove to be a fundamental mechanism for regulating population movements during hematolymphoid development. It will be of interest to determine whether this novel paradigm applies to the migration of stem cells during embryogenesis, the seeding of pro T cells to the thymus, and the redistribution of mature B cells from the bone marrow to the periphery. Moreover, characterization of chemokines and receptors participating in such developmental transitions may provide novel targets for manipulation of the immune system.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. James J. Campbell, Veterans Affairs Medical Center, 3801 Miranda Avenue, Mail Code 154B, Palo Alto, CA 94304. E-mail address:
3 Abbreviations used in this paper: SP, single positive; TECK, thymus-expressed chemokine; MDC, macrophage-derived chemokine; TARC, thymus and activation-regulated chemokine; SLC, secondary lymphoid-tissue chemokine; MIP-3ß, macrophage inflammatory protein-3ß, SDF1, stromal cell-derived factor 1; rmu, recombinant mouse; PNA, peanut agglutinin; DP, double positive.
4 R. A. Warnock, J. J. Campbell, M. E. Dorf, L. M. McEvoy, and E. C. Butcher. 1999. Distinct venular sites and chemokine/adhesion triggering requirements for T versus B cell recognition of Peyer’s patch high endothelial venules: segmental control of vascular arrest as the first step in microenvironmental targeting of lymphoid subsets. Submitted for publication.
5 J. V. Stein, A. Rot, M. Narasimhaswamy, H. Nakano, Y. Luo, M. D. Gunn, A. Matsuzawa, E. J. Quackenbush, M. E. Dorf, and U. H. vonAndrian. 1999. The cc chemokine TCA-4 (SLC, 6CKine, Exodus-2) triggers LFA-1-mediated arrest of rolling T lymphocytes in peripheral lymph node high endothial venules. Submitted for publication.
Received for publication September 22, 1998. Accepted for publication June 16, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
- or lipopolysaccharide-induced expression of the murine P-selectin gene in endothelial cells involves novel 
B sites and a variant activating transcription factor/cAMP response element. J. Biol. Chem. 273:10068.This article has been cited by other articles:
|
|
 |
|
  D. A. Mendes-da-Cruz, S. Smaniotto, A. C. Keller, M. Dardenne, and W. Savino Multivectorial Abnormal Cell Migration in the NOD Mouse Thymus J. Immunol., April 1, 2008; 180(7): 4639 - 4647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Svensson, J. Marsal, H. Uronen-Hansson, M. Cheng, W. Jenkinson, C. Cilio, S. E. W. Jacobsen, E. Sitnicka, G. Anderson, and W. W. Agace Involvement of CCR9 at multiple stages of adult T lymphopoiesis J. Leukoc. Biol., January 1, 2008; 83(1): 156 - 164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. M. Davalos-Misslitz, T. Worbs, S. Willenzon, G. Bernhardt, and R. Forster Impaired responsiveness to T-cell receptor stimulation and defective negative selection of thymocytes in CCR7-deficient mice Blood, December 15, 2007; 110(13): 4351 - 4359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Yin, E. Ladi, S. W. Chan, O. Li, N. Killeen, D. J. Kappes, and E. A. Robey CCR7 Expression in Developing Thymocytes Is Linked to the CD4 versus CD8 Lineage Decision J. Immunol., December 1, 2007; 179(11): 7358 - 7364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bai, H. Hu, M. Yeung, and J. Chen Kruppel-Like Factor 2 Controls T Cell Trafficking by Activating L-Selectin (CD62L) and Sphingosine-1-Phosphate Receptor 1 Transcription J. Immunol., June 15, 2007; 178(12): 7632 - 7639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Lee, S. G. Kang, and C. H. Kim FoxP3+ T Cells Undergo Conventional First Switch to Lymphoid Tissue Homing Receptors in Thymus but Accelerated Second Switch to Nonlymphoid Tissue Homing Receptors in Secondary Lymphoid Tissues J. Immunol., January 1, 2007; 178(1): 301 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-i. Tsukumo, K. Hirose, Y. Maekawa, K. Kishihara, and K. Yasutomo Lunatic Fringe Controls T Cell Differentiation through Modulating Notch Signaling J. Immunol., December 15, 2006; 177(12): 8365 - 8371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ishizaki, A. Togawa, M. Tanaka-Okamoto, K. Hori, M. Nishimura, A. Hamaguchi, T. Imai, Y. Takai, and J. Miyoshi Defective Chemokine-Directed Lymphocyte Migration and Development in the Absence of Rho Guanosine Diphosphate-Dissociation Inhibitors {alpha} and beta J. Immunol., December 15, 2006; 177(12): 8512 - 8521. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Scimone, I. Aifantis, I. Apostolou, H. von Boehmer, and U. H. von Andrian A multistep adhesion cascade for lymphoid progenitor cell homing to the thymus PNAS, May 2, 2006; 103(18): 7006 - 7011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Uehara, S. M. Hayes, L. Li, D. El-Khoury, M. Canelles, B. J. Fowlkes, and P. E. Love Premature Expression of Chemokine Receptor CCR9 Impairs T Cell Development J. Immunol., January 1, 2006; 176(1): 75 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Zubkova, H. Mostowski, and M. Zaitseva Up-Regulation of IL-7, Stromal-Derived Factor-1{alpha}, Thymus-Expressed Chemokine, and Secondary Lymphoid Tissue Chemokine Gene Expression in the Stromal Cells in Response to Thymocyte Depletion: Implication for Thymus Reconstitution J. Immunol., August 15, 2005; 175(4): 2321 - 2330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang, M. J. Finegold, Y. Jin, and M. X. Wu Accelerated transition from the double-positive to single-positive thymocytes in G{alpha}i2-deficient mice Int. Immunol., March 1, 2005; 17(3): 233 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Barbee and J. Alberola-Ila Phosphatidylinositol 3-Kinase Regulates Thymic Exit J. Immunol., February 1, 2005; 174(3): 1230 - 1238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. E. Mick, T. K. Starr, T. M. McCaughtry, L. K. McNeil, and K. A. Hogquist The Regulated Expression of a Diverse Set of Genes during Thymocyte Positive Selection In Vivo J. Immunol., November 1, 2004; 173(9): 5434 - 5444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ueno, F. Saito, D. H.D. Gray, S. Kuse, K. Hieshima, H. Nakano, T. Kakiuchi, M. Lipp, R. L. Boyd, and Y. Takahama CCR7 Signals Are Essential for Cortex-Medulla Migration of Developing Thymocytes J. Exp. Med., August 16, 2004; 200(4): 493 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Witt and E. A. Robey The Ins and Outs of CCR7 in the Thymus J. Exp. Med., August 16, 2004; 200(4): 405 - 409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Yopp, S. Fu, S. M. Honig, G. J. Randolph, Y. Ding, N. R. Krieger, and J. S. Bromberg FTY720-Enhanced T Cell Homing Is Dependent on CCR2, CCR5, CCR7, and CXCR4: Evidence for Distinct Chemokine Compartments J. Immunol., July 15, 2004; 173(2): 855 - 865. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Badolato Leukocyte circulation: one-way or round-trip? Lessons from primary immunodeficiency patients J. Leukoc. Biol., July 1, 2004; 76(1): 1 - 6. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. Staton, B. Johnston, E. C. Butcher, and D. J. Campbell Murine CD8+ Recent Thymic Emigrants are {alpha}E Integrin-Positive and CC Chemokine Ligand 25 Responsive J. Immunol., June 15, 2004; 172(12): 7282 - 7288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Savino, D. A. Mendes-da-Cruz, S. Smaniotto, E. Silva-Monteiro, and D. M. S. Villa-Verde Molecular mechanisms governing thymocyte migration: combined role of chemokines and extracellular matrix J. Leukoc. Biol., June 1, 2004; 75(6): 951 - 961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kwan and N. Killeen CCR7 Directs the Migration of Thymocytes into the Thymic Medulla J. Immunol., April 1, 2004; 172(7): 3999 - 4007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Efroni, D. Harel, and I. R. Cohen Toward Rigorous Comprehension of Biological Complexity: Modeling, Execution, and Visualization of Thymic T-Cell Maturation Genome Res., November 1, 2003; 13(11): 2485 - 2497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Plotkin, S. E. Prockop, A. Lepique, and H. T. Petrie Critical Role for CXCR4 Signaling in Progenitor Localization and T Cell Differentiation in the Postnatal Thymus J. Immunol., November 1, 2003; 171(9): 4521 - 4527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Conroy, L. A. Jopling, C. M. Lloyd, M. R. Hodge, D. P. Andrew, T. J. Williams, J. E. Pease, and I. Sabroe CCR4 blockade does not inhibit allergic airways inflammation J. Leukoc. Biol., October 1, 2003; 74(4): 558 - 563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nasreen, T. Ueno, F. Saito, and Y. Takahama In Vivo Treatment of Class II MHC-Deficient Mice with Anti-TCR Antibody Restores the Generation of Circulating CD4 T Cells and Optimal Architecture of Thymic Medulla J. Immunol., October 1, 2003; 171(7): 3394 - 3400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Rosen, C. Alfonso, C. D. Surh, and M. G. McHeyzer-Williams Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist PNAS, September 16, 2003; 100(19): 10907 - 10912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Johnston, C. H. Kim, D. Soler, M. Emoto, and E. C. Butcher Differential Chemokine Responses and Homing Patterns of Murine TCR{alpha}{beta} NKT Cell Subsets J. Immunol., September 15, 2003; 171(6): 2960 - 2969. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Crittenden, M. Gough, K. Harrington, K. Olivier, J. Thompson, and R. G. Vile Expression of Inflammatory Chemokines Combined with Local Tumor Destruction Enhances Tumor Regression and Long-term Immunity Cancer Res., September 1, 2003; 63(17): 5505 - 5512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lugering, T. Kucharzik, D. Soler, D. Picarella, J. T. Hudson III, and I. R. Williams Lymphoid Precursors in Intestinal Cryptopatches Express CCR6 and Undergo Dysregulated Development in the Absence of CCR6 J. Immunol., September 1, 2003; 171(5): 2208 - 2215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ara, M. Itoi, K. Kawabata, T. Egawa, K. Tokoyoda, T. Sugiyama, N. Fujii, T. Amagai, and T. Nagasawa A Role of CXC Chemokine Ligand 12/Stromal Cell-Derived Factor-1/Pre-B Cell Growth Stimulating Factor and Its Receptor CXCR4 in Fetal and Adult T Cell Development in Vivo J. Immunol., May 1, 2003; 170(9): 4649 - 4655. [Abstract] [Full Text] [PDF]
|
|
