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*
Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115;
Johns Hopkins School of Medicine, Baltimore, MD 21205;
Department of Microbiology, Emory University, GA 30322;
§
Viral Immunology Section, National Institutes of Health, Bethesda, MD 20892;
¶
Beckman Coulter, Miami, FL 33116; and
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Department of Medicine, University of the West Indies, Kingston, Jamaica
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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-chain. Additionally, Tax11-19-reactive
CD8+ T cells used one predominant TCR Vß-chain for the
recognition of the HLA-A2/Tax11-19 complex. These data provide direct
evidence for high frequencies of circulating Tax11-19-reactive
CD8+ T cells in patients with HTLV-I-associated
myelopathy. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The characterization of T cell responses to Ag is critical in understanding the pathophysiology of human diseases induced by chronic viral infections. In humans, this has been hampered by the need to expand Ag-specific T cells in vitro to large numbers to examine their function. However, the process of cloning T cells may irreversibly alter their function (6). For example, activated T cells may selectively undergo activation-induced cell death by in vitro Ag stimulation (7). A recent major advance has been the generation of MHC/peptide tetramers or MHC/Ig fusion proteins that can directly bind the TCR (8, 9). The new technology allows direct analysis of Ag-specific T cells without in vitro manipulation. Direct visualization of Ag-specific CD8+ cells in HIV and EBV infection revealed a high frequency of activated virus-specific CD8+ T cells, a frequency at least two orders of magnitude higher than that expected by LDA (10). Similarly, staining with soluble MHC class I complexes revealed high frequencies of Ag-specific CD8+ cells in animal models of viral infection (10, 11). The use of a soluble MHC/Ig fusion protein for visualization of virus-specific CD8+ T cells similarly revealed high frequencies of cells in HAM/tropical spastic paraparesis patients (12).
Here, we analyzed in detail the activation state, chemokine receptor
expression and TCR usage of HLA-A2/Tax11-19-binding T cells in patients
with HAM. Circulating Tax11-19-reactive T cells were high in frequency,
approaching 1:10 circulating CD8+ T cells, and were
expressing chemokine receptors and the IL-2R ß-chain but not the
IL-2R -chain. Nevertheless, the phenotype of Tax11-19-reactive T
cells was surprisingly heterogeneous, being found equally in both
CD28-positive or -negative and CD45RO or CD45RA populations. Moreover,
Tax11-19-reactive CD8+ T cells were shown to use one
predominant TCR Vß-chain in the recognition of Tax11-19 peptide.
These data provide direct evidence for high frequencies of circulating
Tax11-19-reactive T cells in patients with HAM.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Blood was obtained from four patients with typical HAM. The
patients were residents of Jamaica, West Indies, and expressed the
HLA-A2 phenotype. Blood was also obtained from healthy controls
expressing the HLA-A2 phenotype. Human subjects approval for blood
drawing was obtained from the Brigham and Women’s Hospital and
University of the West Indies, Jamaica Institutional Review Board
committees. A summary of patient clinical data is presented in Table I
.
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HLA-A2 heavy chain and ß2-microglobulin were produced as inclusion bodies in Escherichia coli XA90 carrying either the pHN1-A2BT or the pHN1-ß2-microglobulin plasmid. The inclusion bodies were purified and dissolved in urea denaturing buffer. The monomeric MHC-peptide complexes were formed by combining the A2BT, ß2-microglobulin, and the nonapeptide Tax11-19 in an arginine-folding buffer. The complex was purified using a Sephacryl S300 column (Pharmacia, Piscataway, NJ). The MHC-peptide complex was biotinylated enzymatically with BirA enzyme (Avidity, Denver, CO), and purified on a Mono-Q ion exchange column using a salt gradient (Pharmacia). Neutravidin-R-phycoerythrin (PE) conjugate (Molecular Probes, Eugene, OR) was added to form the tetrameric reagent, which was purified on a Sephacryl S300 column and concentrated.
Isolation of PBMC
PBMCs were isolated by Ficoll/Hypaque (Pharmacia, Uppsala, Sweden) density gradient centrifugation followed by two washings in RPMI 1640 medium. Cells were resuspended at a concentration 5 x 106/ml in PBS medium containing 1% FBS (Sigma, St. Louis, MO). PBMC were stored in liquid nitrogen.
CD8+ T cell clones
The generation of HTLV-I and proteolipid protein reactive CD8+ T cell clones used to assess the specificity of binding of HLA-A2/Tax11-19 tetramer has been previously described (13, 14).
Staining and phenotypic analysis of Tax11-19-specific CD8+ T cells
A total of 2 x 105 PBMC were incubated with 1 µg of PE-conjugated tetrameric complex at 4°C for 1 h. The mAbs used were: anti-CCR2, anti-CXCR3, CXCR1-FITC, anti-CXCR2-FITC, anti-CCR5-FITC (R & D Systems, Minneapolis, MN), anti-CD45RO-FITC, anti-CD45RA-FITC, anti-perforin, anti-RANTES, anti-CD80-FITC, anti-CD8+ Cy, (PharMingen, San Diego, CA), anti-CD2, anti-CD4, anti-CD25, anti-CD122, and anti-CD28 (all from Coulter, Immunotech, FL). When directly labeled Abs were used, cells were incubated with a mixture containing PE-labeled tetramer, FITC-labeled surface Ab, and cychrome-labeled anti-CD8. Indirect staining was completed by incubation of cells with goat anti-mouse IgG-FITC (Biosource, Camarillo, CA) and after washings by a 30-min incubation with anti-CD8-cychrome. Cells were then washed, resuspended in 1% formaldehyde (Sigma), and analyzed on a flow cytometer (Becton Dickinson, San Jose, CA). For staining of intracellular proteins, PBMC were first incubated with tetramer complex, washed, and fixed in 4% paraformaldehyde in PBS for 20 min on ice. After washing, PBMCs were permeabilized in a buffer containing 1% FBS and 0.1% saponin (permeabilization buffer) (Sigma) and incubated with anti-RANTES or anti-perforin Abs for 30 min at 4°C. After washing, PBMC were incubated with goat anti-mouse IgG-FITC F(ab')2. PBMCs were than washed and resuspended in the medium without saponin.
TCR analysis
For analysis of variable TCR ß-chain usage, PBMC were incubated with HLA-A2/Tax tetramer and specific TCR ß-chain Ab. Abs recognizing TCR Vß 2, 3, 5.1, 5.2, 5.3, 6.1, 8, 9, 11, 12, 13.1, 13.6, 14, 16, 17, 18, 20, 21.3, 22 and 23 were used, all from Immunotech (Marseille, France). PBMCs were initially incubated for 1 h at 4°C with HLA-A2/Tax tetramer conjugated with PE and after two washings, with the appropriate anti-TCR Vß Ab, as previously described (15). TCR Vß staining was visualized by incubation of cells with FITC-conjugated anti-mouse IgG F(ab')2 (Biosource) for 30 min at 4°C. PBMC were then stained with anti-human CD8-cychrome.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The specificity of tetramer binding to Ag-specific TCRs was
compared using a HLA-A2-restricted CD8+ T cell clone
reactive with either Tax11-19 or a proteolipid protein-reactive T cell
clone recognizing peptide 80–88. Whereas there was significant binding
of the Tax11-19 PE tetramer to the Tax-specific T cell clone, there was
no binding observed by the Tax11-19 tetramer to the proteolipid
protein-reactive T cell clone (Fig. 1). Similarly, the Tax-reactive T cell
clone bound an HLA-A2 Ig fusion protein loaded with Tax11-19, whereas
no binding was observed when the HLA-A2 Ig fusion protein was loaded
with an irrelevant peptide M1 (Fig. 1C). The HLA-A2/Tax11-19
complexes coupled to PE showed the highest intensity of staining and
were used for the remainder of the experiments.
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Previous analyses of the frequency of Ag-specific T cells relied
upon the ability to expand T cells or measure their function, or both,
in LDAs. A more direct approach where the frequency of T cells was
measured by PCR analysis of TCR - and ß-chains suggested that
assays based upon the ability to grow cells in vitro may underestimate
the frequencies of Ag-specific cells (6). The expansion of
CD8+ T cells in patients with HAM has thus far been based
on LDA. Recently Greten et al. (12), with the use of soluble
HLA-A2/Tax11-19 Ig fusion proteins, reported high frequencies of
virus-specific CD8+ T cells in HAM/tropical spastic
paraparesis patients. The use of HLA-A2/Tax11-19 complexes
enabled us to confirm their observations and further characterize the
population of CD8+ T cells recognizing this epitope. In all
patients examined, we detected a population of CD8+ T cells
that exhibited HLA-A2/Tax11-19 binding (Fig. 2). The frequency of cells that bound
HLA-A2/Tax11-19 tetramer was high and ranged from 0.11 to 3.4% of all
lymphocytes, indicating frequencies of between 1:8 to 1:30 of
CD8+ T cells. In marked contrast, HLA-A2/Tax11-19 tetramer
staining of PBMC from HLA-A2-positive and HLA-A2-negative healthy
subjects and HLA-A2-negative subjects with HAM did not demonstrate any
detectable binding to the HLA-A2/Tax11-19 tetramer (Fig. 2).
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Because the HLA-A2/Tax11-19 tetramer allowed direct analysis of
viral-reactive CD8+ T cells without in vitro manipulation,
we analyzed the phenotype of Tax11-19-specific CD8+ T cells
by using mAbs directed against cell surface molecules associated with T
cell functions, including their state of activation (Table II and Fig. 3).
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We first examined whether there was activation of the
CD8+ T cells specific for Tax11-19 as there is chronic
stimulation of the viral-reactive T cells in the HTLV-I-infected
patients. While very few of the CD8+ T cells specific for
Tax11-19 expressed the IL-2R -chain (CD25) in the four patients
tested, they did express high levels of the IL-2R ß-chain (CD122,
Table II
). To verify that IL-2R -chain expression could be increased
with Ag stimulation in this population of T cells, PBMC were cultured
for 24 h with Chinese hamster ovary cells cotransfected
with HLA-A*0201 and either CD80 (B7-1) or CD58 (LFA-3). Significantly
increased expression of the IL-2R -chain was observed, indicating
that the Tax11-19-specific CD8+ T cells were capable of
up-regulating IL-2R -chain upon Ag stimulation (data not shown).
These results are consistent with recent data in murine models of viral
infection, where expression of IL-2R -, ß-, and 
-chains
differed among CD4+ and CD8+ memory T cell
populations (16). That is, the IL-2R ß- but not the -chain was
selectively expressed in CD8+CD44high cells, a
T cell population that is induced to proliferate by viruses. These data
may indicate that in humans chronic viral activation of
CD8+ T cells is associated with expression of predominantly
the IL-2R ß- but not -chain. Thus, when Tax11-19-specific
CD8+ T cells are activated by the virus, the expression of
CD25 may be more transient, consistent with the observation that
CD8+ T cells recruited to the brain after viral challenge
express low levels of CD25 (17). Because CD122 may also bind IL-15,
increased expression of CD122 by Tax11-19-specific CD8+ T
cells may be associated with the expression of the IL-15 receptor. This
is of particular interest as Zhang et al. (16) have recently shown that
IL-15 is one of the few cytokines that can cause selective stimulation
of memory-phenotype CD8+ T cells and thus might have a role
in the maintenance of Tax11-19-specific CD8+ T cells.
CD28 and CD80 expression
It has been suggested that CD8+CD28- T
cells represent terminally differentiated effector cells. This is in
part based on investigations of subjects with HIV infection where
virus-specific CTLs were found within the CD28- subset of
CD8+ T cells (18). Direct examination of Tax11-19-reactive
T cells revealed heterogeneous expression of CD28 with two distinct
populations (Table II and Fig. 3). These results are thus consistent
with recent data from patients with HIV infection where the same
expanded clone is found within both the
CD8+CD28+ and
CD8+CD28- T cell populations (19) and in
simian immunodeficiency virus-infected rhesus monkeys where
Gag-specific CD8+ T cells identified by tetramer binding
variably express CD28 (20). Thus, the phenotypic heterogeneity of
CD8+ T cells with a given Ag reactivity may indicate a
functional difference between CD8+CD28+ and
CD8+CD28- T cell populations.
Increased expression of B7-1 (CD80), a ligand for CD28, was also observed on Tax11-19-reactive CD8+ T cells. It has been shown that B7-1 is expressed on the surface of a subset of differentiated T cells (21, 22). Analysis of forward scatter of HLA-A2/Tax11-19 tetramer-binding cells demonstrated that cells were not in blastoid stage, implicating a differentiated phenotype.
Chemokine receptor expression
Because Tax11-19-specific CD8+ T cells may migrate to inflammatory central nervous system lesions and thus may potentially be involved in the pathogenesis of HAM, we examined whether these cells expressed chemokine receptors. This was of interest as chemokine receptors are essential for recruitment of circulating leukocytes into sites of inflammation. Moreover, in addition to their role in cell diapedesis, expression of particular chemokine receptors is related to the activation state of the T cell and may also be associated with inflammatory responses.
The chemokine receptors were preferentially expressed on
Tax11-19-specific CD8+ T cells when compared with the total
CD8+ population (Table II). The two patients with the
highest frequency of Tax11-19-specific CD8+ T cells
(patients HAM 1 and 28, Table II) demonstrated a preferential increase
in the expression of CXCR3 when compared with the total
CD8+ population in these patients. Indeed, CXCR3 expression
in Tax11-19-specific CD8+ T cells may characterize a
subpopulation of clonally expanded cells with a high migratory
potential. CXCR3 receptors are involved in T cell adhesion under
conditions of flow (23) and are expressed on CD8+ cells in
perivascular lesions in the brains of macaques with simian
immunodeficiency virus encephalitis (24). In addition, CXCR3
receptors appear to define activated effector/memory T cells and are
expressed on Th0 and Th1 cells; in particular, Th1 cells that are
involved in inflammatory reactions (25, 26). Moreover, patients HAM 1
and 28 also demonstrated increased expression of IL-8 receptors A and B
(CXCR1 and CXCR2, respectively). IL-8 is a major mediator of acute
inflammation, and the receptors CXCR1 and CXCR2 are restricted to
CD8+ T cells, NK cells, and monocytes, although expression
can be variable between different individuals (27).
The Tax11-19-specific CD8+ T cells demonstrated a relative
increase in expression of CCR5 in patients HAM 1 and 10 and of CCR2 in
HAM 23 and 28 (Table II). Previously activated peripheral blood T cells
also express CCR5, a chemokine receptor for RANTES and macrophage
inflammatory protein 1 and ß. CCR5 was described as a
marker to distinguish a population of T cells with migratory capacities
(25), is expressed on both Th1 and Th2 cells, and is markedly
influenced by the presence of IL-2 (28). The Tax11-19-reactive
CD8+ T cells also expressed intracytoplasmic RANTES, a T
cell chemoattractant considered to be an important mediator of
inflammation associated with a Th1 type immune response (29).
These experiments, in total, support data derived from HTLV-I-specific CTL clones isolated from patients with HAM, which have also been shown to secrete proinflammatory cytokines, chemokines, and matrix metalloproteinases in vitro (30). Thus, there may be a relation between activation, cytokine production, and migratory potential of Tax11-19-specific CD8+ T cells. Moreover, the generally high levels of chemokine receptors expressed on Tax11-19-reactive CD8+ T cells indicates that these cells are differentiated and have a potential to migrate into the peripheral tissues. The variable degree of expression among the different chemokine receptors for each subject is consistent with previously published observations of variability in chemokine receptor expression in the general population.
CD45 isoform expression
Significant numbers (40–75%) of Tax11-19-specific CD8+ T cells expressed CD45RO, though in some patients there were also significant numbers of Ag-reactive T cells expressing CD45RA. Although naive T cells that do not respond to recall Ags express the CD45RA isoform of the CD45 complex and T cells recognizing recall Ags are found in the CD45RO population, activated and differentiated T cell clones frequently express both CD45RA and CD45RO Ags (31, 32). Thus, it is likely that at least some of the Tax11-19-reactive CD8+ T cells coexpress both CD45 isoforms and represent activated T cells. These data are consistent with the observation that there is an accumulation of CD8+CD45RO+ lymphocytes in the spinal cord lesions of HAM patients, which correlated with the duration of the disease (33, 34).
TCR repertoire of HLA-A2/Tax-specific CD8+ cells
To examine whether Tax11-19-specific CD8+ T cells
preferentially used a particular TCR Vß-chain, PBMC from patients HAM
1 and HAM 28 were costained with the HLA-A2/Tax11-19 tetramer together
with a panel of anti-TCR Vß mAbs (Fig. 4). In both patients, one type of TCR
Vß-chain predominated: 86% of Tax11-19-reactive CD8+
cells expressed TCR Vß12 in patient HAM 1, and this was paralleled by
expansion of TCR Vß12 T cells in the total CD8+
population (75%). In contrast, 77% of Tax11-19-specific
CD8+ cells expressed the TCR Vß16 in patient HAM 28,
whereas in the total CD8+ population TCR Vß9 predominated
(35% of all CD8). In addition, minor populations of Tax11-19-specific
cells expressed TCR Vß8, 9, 21.3, and 22 in HAM 1, and TCR Vß9, 12,
and 5.1 in HAM 28.
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). However, TCR Vß expansion of
CD8+ population can occur in a substantial number of
healthy individuals (35), and these generally represent
CD8+ T cells recognizing MHC class I-restricted peptides.
Thus, the expansion of CD8+ T cells bearing Vß9 observed
in the CD8+ population of patient HAM 28 may imply a
response to other epitopes of either the Tax protein or of other
HTLV-I-encoded proteins, or instead may represent
CD8+ T cells recognizing other unrelated Ags. In summary, the use of HLA-A2/Tax11-19 tetramer complexes for visualization of Ag-specific CD8+ T cells demonstrated a high frequency of Ag-reactive T cells in patients with HAM. As expected, there was an expansion of Ag-reactive T cells with preferential use of a particular TCR. Surprisingly, populations of CD8+ T cells recognizing the Tax11-19 epitope were heterogeneous in terms of expression of CD28, CD45 isoforms, and different chemokine receptors. These data demonstrate the functional heterogeneity of Ag-reactive T cells in patients with a chronic viral infection.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David A. Hafler, Center for Neurological Diseases, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address:
3 Abbreviations used in this paper: HTLV-I, human T cell lymphotropic virus type I; HAM, HTLV-1-associated myelopathy; LDA, limiting dilution analysis; PE, phycoerythrin.
Received for publication August 19, 1998. Accepted for publication October 14, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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, MIP-1ß, and RANTES is associated with a type 1 response. J. Immunol. 157:3598.[Abstract]
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Z. W. Chen, Y. Li, X. Zeng, M. J. Kuroda, J. E. Schmitz, Y. Shen, X. Lai, L. Shen, and N. L. Letvin The TCR Repertoire of an Immunodominant CD8+ T Lymphocyte Population J. Immunol., April 1, 2001; 166(7): 4525 - 4533. [Abstract] [Full Text] [PDF]
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C. L. Rosa, R. Krishnan, S. Markel, J. P. Schneck, R. Houghten, C. Pinilla, and D. J. Diamond Enhanced immune activity of cytotoxic T-lymphocyte epitope analogs derived from positional scanning synthetic combinatorial libraries Blood, March 15, 2001; 97(6): 1776 - 1786. [Abstract] [Full Text] [PDF]
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M. Saito, G. P. Taylor, A. Saito, Y. Furukawa, K. Usuku, J. N. Weber, M. Osame, and C. R. M. Bangham In Vivo Selection of T-Cell Receptor Junctional Region Sequences by HLA-A2 Human T-Cell Lymphotropic Virus Type 1 Tax11-19 Peptide Complexes J. Virol., January 15, 2001; 75(2): 1065 - 1071. [Abstract] [Full Text]
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S. M. Smith, R. Brookes, M. R. Klein, A. S. Malin, P. T. Lukey, A. S. King, G. S. Ogg, A. V. S. Hill, and H. M. Dockrell Human CD8+ CTL Specific for the Mycobacterial Major Secreted Antigen 85A J. Immunol., December 15, 2000; 165(12): 7088 - 7095. [Abstract] [Full Text] [PDF]
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D.-G. Lim, K. Bieganowska Bourcier, G. J. Freeman, and D. A. Hafler Examination of CD8+ T Cell Function in Humans Using MHC Class I Tetramers: Similar Cytotoxicity but Variable Proliferation and Cytokine Production Among Different Clonal CD8+ T Cells Specific to a Single Viral Epitope J. Immunol., December 1, 2000; 165(11): 6214 - 6220. [Abstract] [Full Text] [PDF]
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S. R. Burrows, N. Kienzle, A. Winterhalter, M. Bharadwaj, J. D. Altman, and A. Brooks Peptide-MHC Class I Tetrameric Complexes Display Exquisite Ligand Specificity J. Immunol., December 1, 2000; 165(11): 6229 - 6234. [Abstract] [Full Text] [PDF]
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S. M. Varga, E. L. Wissinger, and T. J. Braciale The Attachment (G) Glycoprotein of Respiratory Syncytial Virus Contains a Single Immunodominant Epitope That Elicits Both Th1 and Th2 CD4+ T Cell Responses J. Immunol., December 1, 2000; 165(11): 6487 - 6495. [Abstract] [Full Text] [PDF]
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 A. L. Meyer, C. Trollmo, F. Crawford, P. Marrack, A. C. Steere, B. T. Huber, J. Kappler, and D. A. Hafler Direct enumeration of Borrelia-reactive CD4 T cells ex vivo by using MHC class II tetramers PNAS, September 22, 2000; (2000) 190335897. [Abstract] [Full Text]
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M.-B. Nielsen, V. Monsurro, S. A. Migueles, E. Wang, A. Perez-Diez, K.-H. Lee, U. Kammula, S. A. Rosenberg, and F. M. Marincola Status of Activation of Circulating Vaccine-Elicited CD8+ T Cells J. Immunol., August 15, 2000; 165(4): 2287 - 2296. [Abstract] [Full Text] [PDF]
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J.-F. Baurain, D. Colau, N. van Baren, C. Landry, V. Martelange, M. Vikkula, T. Boon, and P. G. Coulie High Frequency of Autologous Anti-Melanoma CTL Directed Against an Antigen Generated by a Point Mutation in a New Helicase Gene J. Immunol., June 1, 2000; 164(11): 6057 - 6066. [Abstract] [Full Text] [PDF]
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E. Hanon, S. Hall, G. P. Taylor, M. Saito, R. Davis, Y. Tanaka, K. Usuku, M. Osame, J. N. Weber, and C. R. M. Bangham Abundant Tax protein expression in CD4+ T cells infected with human T-cell lymphotropic virus type I (HTLV-I) is prevented by cytotoxic T lymphocytes Blood, February 15, 2000; 95(4): 1386 - 1392. [Abstract] [Full Text] [PDF]
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 C. Pique, A. Ureta-Vidal, A. Gessain, B. Chancerel, O. Gout, R. Tamouza, F. Agis, and M.-C. Dokhelar Evidence for the Chronic in Vivo Production of Human T Cell Leukemia Virus Type I Rof and Tof Proteins from Cytotoxic T Lymphocytes Directed against Viral Peptides J. Exp. Med., February 7, 2000; 191(3): 567 - 572. [Abstract] [Full Text] [PDF]
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B. L. Kotzin, M. T. Falta, F. Crawford, E. F. Rosloniec, J. Bill, P. Marrack, and J. Kappler Use of soluble peptide-DR4 tetramers to detect synovial T cells specific for cartilage antigens in patients with rheumatoid arthritis PNAS, January 4, 2000; 97(1): 291 - 296. [Abstract] [Full Text] [PDF]
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S. J. Youde, P. R. R. Dunbar, E. M. L. Evans, A. N. Fiander, L. K. Borysiewicz, V. Cerundolo, and S. Man Use of Fluorogenic Histocompatibility Leukocyte Antigen-A*0201/HPV 16 E7 Peptide Complexes to Isolate Rare Human Cytotoxic T-Lymphocyte- recognizing Endogenous Human Papillomavirus Antigens Cancer Res., January 1, 2000; 60(2): 365 - 371. [Abstract] [Full Text]
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K.-H. Lee, E. Wang, M.-B. Nielsen, J. Wunderlich, S. Migueles, M. Connors, S. M. Steinberg, S. A. Rosenberg, and F. M. Marincola Increased Vaccine-Specific T Cell Frequency After Peptide-Based Vaccination Correlates with Increased Susceptibility to In Vitro Stimulation But Does Not Lead to Tumor Regression J. Immunol., December 1, 1999; 163(11): 6292 - 6300. [Abstract] [Full Text] [PDF]
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 P. Hollsberg Mechanisms of T-Cell Activation by Human T-Cell Lymphotropic Virus Type I Microbiol. Mol. Biol. Rev., June 1, 1999; 63(2): 308 - 333. [Abstract] [Full Text] [PDF]
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A. L. Meyer, C. Trollmo, F. Crawford, P. Marrack, A. C. Steere, B. T. Huber, J. Kappler, and D. A. Hafler Direct enumeration of Borrelia-reactive CD4 T cells ex vivo by using MHC class II tetramers PNAS, October 10, 2000; 97(21): 11433 - 11438. [Abstract] [Full Text] [PDF]
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