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ß T Cell Repertoire1
,
,§,,§
*
Department of Medicine, Committee on Immunology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637; Departments of
Medicine and
Microbiology and Immunology, and
§
Howard Hughes Medical Institute, University of California, San Francisco, CA 94143; and
¶
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-ß
Leishmania-specific (ABLE) TCR transgenic mice with MHC
class II-restricted T cells that recognized an immunodominant
Leishmania Ag designated LACK. Naive T cells from ABLE mice
proliferated in vitro after incubation with recombinant LACK or with
Leishmania-parasitized macrophages and in vivo after
injection into infected mice. Infected ABLE mice controlled
Leishmania infection almost as well as wild-type mice
despite a drastic reduction in the T cell repertoire. ABLE mice were
crossed to mice with disruption of the TCR constant region gene to
create animals with a single ß T cell repertoire. Although mice
deficient in all ß T cells (TCR-Co mice) failed to
control L. major, mice with a monoclonal ß T cell
repertoire (ABLE TCR-Co mice) displayed substantial
control. The immune system is capable of remarkable efficiency even
when constrained to recognition of a single epitope from a complex
organism. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T cells are required
for resistance (2, 3, 4), MHC class I-restricted T cells are dispensable
(5). IL-12 (6), IFN-
(7, 8), and inducible (macrophage) nitric oxide
synthase (9) are required for host immunity, perhaps reflecting
activities mediated by CD40 ligand-CD40 interactions between T cells
and APC (10, 11, 12). These numerous experiments suggest that MHC class
II-restricted Th1 effector cells and activated macrophages are
necessary and sufficient for control of this intracellular
infection.
Although these host determinants have been established, the complexity
of the Ags presented by the parasite that are necessary for control of
disease remains unknown. Numerous Ags provide lesser or better, but
generally incomplete, protection when used as vaccines against
subsequent challenge with virulent Leishmania (reviewed in
13 . It is unclear whether optimal protection requires a diverse
response against numerous parasite Ags or an optimal response against
single, dominant, determinants. Such understanding may have important
implications for vaccine design. We have created TCR transgenic mice
with MHC class II-restricted T cells that recognize the
LACK4 Ag of
Leishmania major (14). LACK is highly conserved
among Leishmania species, and constitutes the immunodominant
focus of the early CD4+ T cell response in vivo (15).
Crossing these mice to animals with disruption of the TCR C gene
(TCR-Co) (16) created mice with a single ß T cell
repertoire. These mice were used to assess the requirements for a
diverse pathogen-specific T cell repertoire in a disease controlled by
MHC class II-restricted T cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The rearranged and ß TCR genes were isolated from a
CD4+ Th1 clone, 9.1-2, that was isolated from a BALB/c
mouse that had been immunized with soluble Ags of L. major
(17). Clone 9.1-2 expresses rearranged TCR gene segments
V8.2A-JTA72 and Vß4-Dß1-Jß1.6 (15). Primers specific for
the 5' region of V8.2A and Vß4 were used in conjunction with
antisense primers from the introns beyond JTA72 and Jß1.7,
respectively, to amplify the rearranged V(D)J portions of genomic DNA
extracted from clone 9.1-2. The 5' portion of each TCR transgene
construct containing the 5' untranslated and initial coding region of
each V gene was subcloned from cosmids obtained from a BALB/c genomic
library (provided by K. Wang and L. Hood, California Institute of
Technology, Pasadena, CA). The 5' portions were spliced into the V(D)J
PCR products using unique sites within the V genes of the TCR - and
ß-chains (PstI and SalI, respectively).
The TCR -chain transgene was completed by appending a 9-kb
BamHI fragment of the C locus (provided by D. Loh,
Washington University, St. Louis, MO) containing 0.8 kb of upstream
intron, the entire coding region, and the downstream enhancer to the 3'
end of the promoter-V-J-intron construct. The TCR ß-chain transgene
was completed by appending a Cß1 and downstream ß-chain enhancer
construct (provided by S. Hedrick, University of California-San Diego)
to the 3' end of the promoter-V-D-J-intron construct at the Jß-Cß
intron using a naturally occurring NsiI site.
Equimolar concentrations of gel-purified constructs were injected into
the pronuclei of [C57BL/6 x DBA/2] F1 eggs that had
been fertilized by BALB/c males before implantation in pseudopregnant
recipients. One of three founders that expressed Vß4 on all
peripheral blood T cells was used as the progenitor of the ABLE
transgenic line. Progeny were backcrossed to B10.D2 mice.
Simultaneously, TCR-Co mice (16), which lack all ß
T cells, were backcrossed to B10.D2 mice. After five generations, mice
were intercrossed to yield TCR-C+,
TCR-Co, and ABLE TCR-Co mice on the
B10.D2 background. ABLE mice were crossed to the MHC H-2k haplotype as
a source of naive donor cells in designated experiments.
Reagents
Directly fluorescence-conjugated mAbs against CD4, CD8, CD3, Vß4, and CD69 were used for surface immunofluorescent labeling (Caltag, South San Francisco, CA). Anti-MHC class II Abs used in designated experiments included mAb M5/114 (rat IgG2b, anti-Ab,d and anti-Ed,k), mAb MKD6 (mouse IgG2a, anti-Ad), or mAb 10–2–16 (mouse IgG2b, anti-Ak). The LACK156–173 peptide from the fourth WD domain of the LACK protein (ICFSPSLEHPIVVSGSWD) (14) was synthesized using an Advanced Chemtech Multiple Peptide Synthesizer (Louisville, KY). Peptides were purified by reverse phase HPLC, and their identities were confirmed by analysis with an LCQ mass spectrometer (Finnigan MAT, San Jose, CA). Recombinant LACK protein was expressed in Escherichia coli and purified as previously described (14).
Parasites and infections
L. major (strain WHOM/IR/-/173) was passaged and maintained as previously described (18). Leishmania amazonensis (strain LV-78) was provided by K. P. Chang (Chicago Medical School, Chicago, IL). For the infection of macrophages in vitro, the designated numbers of stationary phase promastigotes were cultured for 24 h with bone marrow-derived macrophages, prepared as previously described (18), in 96-well, flat-bottom, microtiter plates containing 5 x 104 macrophages/well. The monolayers were washed extensively to remove extracellular parasites before addition of T cells (see below).
For in vivo infections, designated cohorts of four to eight mice were inoculated in the hind footpads with 5 x 105 metacyclic promastigotes of L. major prepared as previously described (18). The sizes of the footpad lesions were measured weekly using a metric caliper. Mice were killed after 6 to 10 wk and analyzed as individual animals. The footpad parasite burdens were quantitated by homogenizing tissue in 3 ml of medium 199 supplemented with 20% FCS. Aliquots were diluted serially across 96-well plates and scored at 1 wk for the presence of motile promastigotes.
Amastigotes were purified from the spleens and lymph nodes of
TCR-Co mice that had been infected 10 wk previously with
L. major as previously described (19). Briefly, tissues were
dispersed by repeated forceful expression through a syringe and
27-gauge needle in PBS supplemented with 10 mM glucose and 2 mM EDTA
until free amastigotes were visible by light microscopic analysis of
smeared aliquots. The organisms were recovered after centrifugation
from a 45 to 100% Percoll interface, washed extensively, counted, and
injected into the footpads of naive TCR-Co mice using
5 x 105 organisms/footpad.
Stimulation of ABLE T cells in vitro
Naive ABLE T cells were isolated from lymph nodes of MHC H-2k mice crossed to ABLE transgenic mice. Positive selection of the transgenic T cells occurs in MHC H-2k mice, although H-2k APCs neither present the LACK Ag or peptide in vitro nor stimulate alloreactivity by ABLE T cells (see Results). T cells (4 x 105/well) were placed in triplicate wells containing H-2d (I-Ad+) bone marrow-derived macrophages that had either been infected with Leishmania promastigotes or been incubated with the designated concentrations of the recombinant LACK protein for 24 h. Where designated, irradiated (2000 rad) H-2d spleen cells were used as APCs, using 4 x 105 cells/well. After 48 h, supernatants were collected and analyzed for IL-2 production by ELISA (PharMingen, San Diego, CA). Alternatively, 1 µCi of [3H]thymidine was added to each well, and the radioactivity incorporated was assessed after 18-h additional incubation as an index of T cell proliferation.
ABLE T cells from the popliteal lymph nodes of infected mice were
cultured in triplicate in 96-well round-bottom microtiter plates in
supplemented tissue culture medium (RPMI 1640 with 2 mM
L-glutamine, 0.1 mM sodium pyruvate, 50 µM ß2-ME,
antibiotics, and 10% heat-inactivated FCS) in the presence or the
absence of 5 µM LACK156–173 peptide. In some
experiments, the CD4+ and CD4- ABLE T cells
were enriched into two populations using anti-CD4 mAb coupled to
ferrous beads (Advanced Magnetics, Inc., Cambridge, MA) and separation
in a magnetic field before incubation with the LACK peptide and
irradiated spleen cells at a ratio of 1 T cell:10 spleen cells. After
48 h, supernatants were analyzed for IFN- by ELISA
(PharMingen).
Stimulation of ABLE T cells in vivo
Cohorts of TCR-Co mice that had been
infected with promastigotes or amastigotes of L. major were
reconstituted i.v. with 107 Vß4+ T cells that
were enriched from ABLE mice by complement-mediated lysis of
CD8-, class II- and B220-bearing cells as previously
described (20). The purified cells were >88% Vß4+ T
cells. At designated periods, the popliteal lymph nodes were harvested,
and cells were stained with fluorescent mAbs against CD4, Vß4, and
the activation marker, CD69, for cell surface analysis (FACScan, Becton
Dickinson, Mountain View, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ABLE transgenic mice were normal in size and appearance and had
normal reproductive capacity (data not shown). Homozygous TCR
transgenic animals developed and lived normal life-spans, indicating
that the transgene insertion site did not disrupt an essential gene
(data not shown). Lymphocyte surface markers were examined on cells
from H-2d, age-matched, wild-type, ABLE and ABLE
TCR-Co mice using fluorescence-conjugated mAbs and
flow cytometry. Results were similar using ABLE and ABLE
TCR-Co mice (despite the use of endogenous TCR
-chains in the former), and only the latter are shown (Fig. 1
). Compared with control mice, ABLE
TCR-Co mice had an increase in CD4+
single-positive and a reduction in CD8+ single-positive
thymocytes, consistent with the class II restriction of the TCR. In the
peripheral lymph nodes, control mice had only a small population of
CD3+ cells that expressed Vß4 TCR. In contrast,
essentially all CD3+ cells from the lymph nodes of ABLE and
ABLE TCR-Co mice expressed Vß4 TCR. Analysis of the
CD3+ cells revealed the expected distribution of CD4 and
CD8 coreceptors in control mice. ABLE TCR-Co
mice had marked reduction in CD8+ T cells, as anticipated,
but unexpectedly, had a reduced number of CD4+ T cells and
a majority population of CD3+ cells that expressed a
CD4-CD8- or a
CD4-CD8dull double-negative (DN) phenotype
(Fig. 1). When bred to the MHC H-2k MHC haplotype, ABLE T cells
developed comparably and displayed both CD4+ and DN
phenotypes (data not shown).
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ABLE T cells were isolated from ABLE-H-2k mice, which support
positive thymic selection and peripheral localization of the ABLE
transgenic T cells. H-2d macrophages that had been infected with either
L. major or L. amazonensis or had been incubated
with the recombinant LACK Ag stimulated IL-2 production from ABLE T
cells in a dose-dependent fashion (Fig. 2A). T cells from
wild-type B10.D2 mice produced no IL-2 in response to LACK peptide or
parasitized macrophages under these conditions (data not shown). Lymph
node cells from the ABLE-H2k mice did not by themselves support IL-2
production by the peptide, demonstrating the inability of H-2k to
present the LACK epitope, and the requirement of LACK Ag for the
production of IL-2 was consistent with the absence of alloreactivity
(Fig. 2B). The specificity of the restriction was
confirmed by the capacity of anti-MHC class II I-Ad mAb
to abrogate IL-2 production (Fig. 2B) and by
Ag-dependent proliferation in response to fibroblasts transfected with
I-Ad (data not shown). Similar results were obtained if T
cell proliferation was assayed using the incorporation of
[3H]thymidine: the mean uptake using ABLE lymph node
cells incubated with the LACK peptide was 46,100 ± 2,300 cpm, and
this decreased to 1,100 ± 880 cpm in the presence of blocking
anti-I-Ad mAb and to 1,250 ± 740 cpm in the
absence of the LACK peptide. The LACK-dependent proliferation,
production of IL-2, and I-Ad restriction could be
demonstrated using both purified CD4+ and DN T cells
isolated from ABLE TCR-Co mice (data not shown).
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Prior studies using LACK-reactive hybridomas have suggested that
amastigotes within macrophages cease to present the LACK epitope with
surface MHC class II molecules (21). To assess this possibility using
ABLE T cells, TCR-Co mice were infected with
amastigotes purified from the lymphoid tissues of previously infected
TCR-Co mice, thus establishing infection only with the
intracellular form of the parasite. A similar cohort was infected with
metacyclic promastigotes. Either the same day or 4 or 28 days later,
animals were reconstituted with 107 Vß4+
CD4+ T cells from ABLE mice. After varying periods, the
popliteal lymph node cells were collected, and the total numbers of
cells were enumerated and stained with mAbs to Vß4, CD4, and CD69
(Table I). By this analysis, large
numbers of the transferred ABLE TCR transgenic T cells expressed the
activation Ag CD69, which was expressed by 5 to 8% of the cells after
transfer into uninfected TCR-Co mice. The acquisition of
CD69 expression occurred after infection with both promastigotes and
amastigotes, and both T cell number and CD69 expression increased in
relation to the duration of the infection. Thus, ABLE T cells became
activated in response to infected macrophages in vitro and in
vivo.
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B10.D2 mice are resistant to L. major and control
infection with the development of small lesions at the site of
inoculation of organisms. After infection, B10.D2 ABLE mice also
displayed control markedly different from that shown by concurrently
inoculated susceptible BALB/c mice (Fig. 3A). Occasional ABLE
mice had some enlargement of the lesions over 10 to 12 wk compared with
B10.D2 controls, but the vast majority had a completely wild-type
phenotype and controlled parasite replication in both the footpad and
spleen (Fig. 3B). Infected ABLE mice developed type 1
immune responses, as assessed by the production of IFN-, but not
IL-4, by peripheral lymph node cells in culture (data not shown). Thus,
restriction of the T cell repertoire to Vß4-expressing cells, many of
which express the clonotypic V8/Vß4 LACK-specific receptor, did
not compromise immunologic control of Leishmania.
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-chains in TCR transgenic
mice and our inability to create a clonotypic mAb, we could not assess
the contributions to host defense by the nonclonotypic T cell
repertoire, e.g., cells that expressed the Vß4 transgene together
with endogenous V-chains. To exclude a role for endogenous TCR
gene products, ABLE mice were crossed to TCR-Co mice,
thus creating animals with a single T cell repertoire that recognized
the LACK determinant. Unlike B10.D2 mice, ß T cell-deficient
B10.D2 mice (TCR-Co) were highly susceptible to L.
major. These mice developed large footpad lesions, displayed loss
of weight associated with systemic dissemination, and had significantly
greater numbers of parasites recovered from the footpads and spleens
than did wild-type animals (Fig. 4,
A and B). In contrast, ABLE
TCR-Co B10.D2 mice more closely resembled wild-type
mice, with normal weight gain and activity, but with small,
nonulcerating, footpad lesions that were approximately 1 mm larger than
those in infected wild-type mice. Further, the number of recovered
parasites from ABLE TCR-Co mice was 1,000-fold greater
than that in wild-type animals, although this was over 10,000-fold
fewer than that in TCR-Co mice. Popliteal lymph node
cells isolated from infected mice and restimulated in vitro with the
LACK peptide produced large amounts of IFN- and negligible
quantities of IL-4, consistent with the development of Th1 effector
cells. When CD4+ and DN cells from the ABLE
TCR-Co mice were enriched, both populations were capable
of generating IFN- in an Ag-dependent manner (Fig. 4C). Thus, substantial disease control was maintained
by a monoclonal repertoire consisting of a single parasite-specific
TCR-ß.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Extensive prior studies have documented the requirements for class
II-restricted T cells in mediating host protection against these
parasites (1). Contributions from the innate immune system or 
T
cells in providing host defense in ABLE TCR-Co mice were
unlikely, as established by the inability of infected
TCR-Co mice to contain disease. The substantial
protection mediated by ABLE T cells may reflect the dominant nature of
the LACK epitope. The Vß4/V8 TCR expressed by ABLE T cells
represents an oligoclonal T cell response that occurred in the lymph
nodes of mice early after infection with L. major (15). This
restricted response may account for the isolation of clone 9.1-2, a Th1
clone established from an immunized BALB/c mouse, that mediated
protection after transfer into lightly irradiated recipients (17).
Importantly, these data establish the capacity of ABLE T cells to alone
mediate protection by differentiation to effector cells in situ, in
contrast to the protection mediated by the adoptive transfer of clone
9.1-2, a fully committed Th1 effector cell, in the setting of a diverse
T cell repertoire (17). The dominant nature of the LACK epitope could
be due to a combination of factors, including Ag abundance, processing,
and stability; MHC affinity; and/or T cell precursor frequency.
The LACK Ag is highly conserved among different species of
Leishmania (14). The immunogenic LACK156–173
epitope was completely conserved, and 9.1-2 cells proliferated after
incubation with APCs that had been primed with soluble extracts from
all species of Leishmania tested (14, 17). As demonstrated
here, this epitope is presented by viable organisms during infection by
different Leishmania species in vitro and in vivo, as
demonstrated by the activation of ABLE T cells after transfer into mice
infected with amastigotes and by the control of disease in ABLE
TCR-Co mice. LACK represents the Leishmania
homologue of RACK1, a membrane-associated protein to which activated
PKC translocates from the cytosol, presumably to establish an
enzymatically active complex (24). In turn, these proteins are members
of the highly conserved WD motif proteins that perform similar
scaffold-like functions critical for numerous intracellular activities
(25). The requirements for binding substrates by distinct domains of
these molecules may underlie both their conserved nature and their
requisite biologic functions. LACK may be an indispensable component of
the organisms’ cell biology that has evolved to provide an invariant
target in the mammalian host.
One peculiar aspect of the ABLE mice was the large numbers of TCR transgene-positive DN cells that occurred in both thymic and peripheral compartments. These cells, which have been noted previously in TCR transgenic mice (discussed in 26 , may arise by an accelerated developmental process in response to premature expression of the rearranged transgene that supports the release of these cells from the thymus before transit through the usual CD4+CD8+, double-positive, stage (20, 26, 27). Despite their unusual lineage, such cells accumulate in the periphery as fully Ag-reactive T cells (26, 27). CD4+ and DN ABLE T cells proliferated in response to the LACK Ag and differentiated to competent effector type 1 cells during infection with L. major, consistent with prior observations regarding the capacity of CD4-deficient Th cells to function as Th1-like cells (4, 20, 28).
One intriguing aspect of the LACK Ag regards the finding that deletion
of the LACK-reactive T cell repertoire, either by thymic expression of
LACK (29) or by superantigen-mediated deletion after infection with
mouse mammary tumor virus (SIM) (30), abrogated the exquisite
susceptibility of BALB/c mice to L. major, thus enabling
infected mice to heal. Thus, recognition of the LACK epitope was not
required to effect a healer phenotype. CD4+ T cells from
BALB/c mice have a genetic propensity to produce more IL-4 during
priming than do T cells from B10.D2 mice (31), a finding that may
reflect extinction of IL-12-mediated signaling in committed T cells
(32). The immunodominant response to LACK coupled with a genetic
tendency to overproduce IL-4 may combine to mediate susceptibility of
BALB/c mice to L. major. Abrogation of the early IL-4
produced in these mice in response to LACK was sufficient to reverse
susceptibility (30), implying that additional Ags from
Leishmania are capable of focusing a protective Th1
response. The absence of reactivity to these additional Ags may explain
the greater parasite burdens that occurred in infected ABLE
TCR-Co compared with those in wild-type, mice.
Reconstitution of ABLE TCR-Co mice with ß T cells
with additional parasite specificities will be useful in determining
the minimal requirements for a fully competent immune response to
complex organisms. Such insights will be important in considering
vaccine approaches using recombinant proteins.
The observation that ABLE mice can sustain protective immune responses to L. major illustrates the ability to use TCR transgenic mice to examine effector T cell differentiation in vivo. To the best of our knowledge, these mice remain the only MHC class II-restricted TCR transgenic mice expressing pathogen-specific receptors. Although studies employing peptide Ags have questioned the fidelity of T cell reactivity in TCR transgenic mice, as assessed in vivo (33), organisms and/or their biologic products often engender responses quite different from those induced by isolated protein reagents (34, 35, 36). The requirements for activation or generation of polarized Th subset responses in vivo may be more readily revealed in the presence of chronic stimulation achieved by persistent infection. The ABLE mice should provide insights into the homing, activation, expansion, maturation, and death of Th cells in response to biologic agents in vivo, much as prior experiments using MHC class I, virus-specific, TCR transgenic mice have provided information regarding cytotoxic T cells (37).
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Acknowledgments |
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Footnotes |
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2 Burroughs Wellcome Fund New Investigator in Molecular Parasitology.
3 Address correspondence and reprint requests to Dr. R. M. Locksley, University of California, C-443, 521 Parnassus Ave., San Francisco, CA 94143–0654. E-mail address:
4 Abbreviations used in this paper: LACK, Leishmania homologue of receptor for activated C kinase; ABLE, /ß Leishmania-specific T cell receptor for antigen transgenic mice; WD, tryptophan-aspartic acid; dull, low level; DN, double negative; PE, phycoerythrin.
Received for publication July 23, 1997. Accepted for publication October 1, 1997.
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antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major. J. Immunol. 143:266.[Abstract]
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R. L. A. Bottrel, W. O. Dutra, F. A. Martins, B. Gontijo, E. Carvalho, M. Barral-Netto, A. Barral, R. P. Almeida, W. Mayrink, R. Locksley, et al. Flow Cytometric Determination of Cellular Sources and Frequencies of Key Cytokine-Producing Lymphocytes Directed against Recombinant LACK and Soluble Leishmania Antigen in Human Cutaneous Leishmaniasis Infect. Immun., May 1, 2001; 69(5): 3232 - 3239. [Abstract] [Full Text] [PDF]
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V. Julia, S. S. McSorley, L. Malherbe, J.-P. Breittmayer, F. Girard-Pipau, A. Beck, and N. Glaichenhaus Priming by Microbial Antigens from the Intestinal Flora Determines the Ability of CD4+ T Cells to Rapidly Secrete IL-4 in BALB/c Mice Infected with Leishmania major J. Immunol., November 15, 2000; 165(10): 5637 - 5645. [Abstract] [Full Text] [PDF]
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K. J. Maloy, C. Burkhart, G. Freer, T. Rulicke, H. Pircher, D. H. Kono, A. N. Theofilopoulos, B. Ludewig, U. Hoffmann-Rohrer, R. M. Zinkernagel, et al. Qualitative and Quantitative Requirements for CD4+ T Cell-Mediated Antiviral Protection J. Immunol., March 1, 1999; 162(5): 2867 - 2874. [Abstract] [Full Text] [PDF]
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