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ß T Cell Pool1
*
Lymphocyte Biology Section, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA 02115; and
Division of Dermatology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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ß+
CD8+ T cells recognize immunogenic peptides bound to
MHC-encoded class I molecules. This recognition is a major component of
the cellular response mediating immune protection and recovery from
viral infections and from certain intracellular bacterial infections.
Here, we report two human CD8+ TCR ß+ T
cell lines specific for Mycobacterium tuberculosis Ags
presented in the context of CD1a or CD1c Ag-presenting molecules. These
T cells recognize lipid Ags and display cytotoxicity as well as strong
Th cell type I cytokine responses. By extending presentation by the CD1
system to the major TCR ß+ CD8+ T cell
pool, this system gains wider applicability beyond the double negative
subset of T cells previously shown to have this reactivity. This
implies that previous assumptions about the role of CD8+ T
cells in microbial immunity may require revision as the relative
proportions of CD1-restricted and MHC class I-restricted
CD8+ T cells are further defined. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Here, we show that CD1-restricted, non-protein, Ag-reactive T cells are
present among the TCR ß+ CD8+ T cells in
human peripheral blood. We describe IL-2-dependent in vitro cultured T
cell lines expressing the CD8 ß heterodimer that were restricted
either by CD1a or CD1c and recognized nonprotein lipid Ags. These T
cells displayed efficient cytotoxicity against Ag-pulsed target cells
as well as Th1 cytokine-producing effector capabilities, suggesting an
important potential for these CD8+ T cells in mediating
host defense.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The T cell lines CD8-1 and CD8-2 were established from random donor peripheral blood. CD8+ T cells were purified from nonadherent mononuclear cells via magnetic cell sorting (Miltenyi Biotec, Auburn, CA) with anti-CD8 microbeads, according to the manufacturer’s instructions. After magnetic separation, the resulting CD8+ T cells (>95% pure, as assessed by FACS analysis) were cultured with a chloroform/methanol extract of Mycobacterium tuberculosis (10 mg dry bacteria/ml extract, dried under nitrogen and resuspended by sonication in complete medium containing 10% FCS, used at 1:2500 final dilution) in the presence of an equal number of monocytes (treated for 3 days with 300 U/ml granulocyte-macrophage CSF (GM-CSF; Immunex, Seattle, WA) and 200 U/ml IL-4 (gift of Schering, Kenilworth, NJ) to induce CD1 expression, hereafter described as CD1+ monocytes (1)). Cultures were restimulated every 10–14 days with CD1+ monocytes (three times with autologous and thereafter with allogeneic APCs). The CD4+ T cell line CD4-1 was derived from peripheral blood by repeated stimulation with autologous, irradiated PBMC and an aqueous sonicate of M. tuberculosis (10 µg protein/ml final). All cultures were replenished every 3–4 days with complete medium (RPMI 1640 with 10% FCS and additional supplements as previously described (7)) and 1 nM recombinant human IL-2 (Ajinomoto, Kawasaki, Japan; Chiron, Emoryville, CA).
FACS analysis
The following biotinylated Abs were used for flow cytometry:
BMA031 (anti-TCR ß, 8 , OKT4 (anti-CD4, 9 , OKT8
(anti CD8, 9 , 2ST8–5H7 (anti-CD8ß, 10 , and 9.3
(anti-CD28, Ref 11). Second step reagent R-phycoerythrin
streptavidin was purchased from Caltag (South San Francisco, CA).
Analyses were performed on a FACSORT (Becton Dickinson, Franklin Lakes,
NJ) as previously described (12).
Proliferation experiments
T cells (5 x 104) and irradiated (5000 rads) CD1+ monocytes (5 x 104) as APCs were cultured in 96-well flat-bottom plates in the presence of Ag. Cultures were collected on day 3 for CD8-1 and CD4-1, and day 4 for CD8-2 and DN1, after a 6 h pulse with 1 µCi/well [3H]thymidine (6.7 Ci/mmol, New England Nuclear, Boston, MA), and [3H]thymidine incorporation was determined by liquid scintillation counting. In the blocking experiments, the following Abs were added to the wells at a 1:200 dilution of ascites: OKT6 (anti-CD1a, 9 , WM-25 (anti-CD1b, 13 , 10C3 (anti-CD1c, 14 , W6/32 (anti-MHC class I, 15 , and IVA12 (anti-MHC class II, 16 .
Cytotoxicity assays
C1R lymphoblastoid cell lines transfected with expression
vectors encoding the CD1a, -b, or -c glycoproteins (17) were labeled
with 51Cr for 4 h as previously described (7). The
target cells (1 x 106) were pulsed overnight with an
organic extract of mycobacteria (1:100 dilution of organic extract, 10
mg/ml dry bacteria equivalent) and washed. The target cells (2 x
103) were plated with T cells at different ratios in a
total volume of 150 µl and incubated for 3 h. Supernatants (25
µl) were harvested and counted in a gamma counter. In preliminary
experiments, we noted that OKT8 and 2ST8–5H7 anti-CD8 mAbs alone
had only marginal effects on cytolysis of targets pulsed with a range
of Ag concentrations. For the experiments described in the text,
TS2/18.1.1 anti-CD2 mAb was included at a concentration (1:4000
dilution of ascites) that alone blocks cytolysis suboptimally.
Cytolysis was blocked by TS2/18.1.1 optimally at a 1:200 dilution of
ascites. In the CD8 blocking experiments, T cells (106/ml)
were preincubated with the following blocking Abs for 1 h:
TS2/18.1.1 (anti-CD2, Ref. 18, 1:4000 ascites dilution), OKT4
(anti-CD4, 1:200), OKT8 (anti CD8, 1:200), and 2ST8-5H7
(anti-CD8ß, 1:200). Target cells (106/ml) were
preincubated with purified mouse Ig (Accurate Chemical & Scientific,
Westbury, NY) and purified human Ig (Caltag) at 10 µg/ml to block Fc
receptors before adding effector cells that had been preincubated with
mAbs.
Ag preparations
Protease-digested M. tuberculosis Ag. An aqueous sonicate of M. tuberculosis was produced by sonication of lyophilized bacilli (strain H37Ra; Difco, Detroit, MI) in PBS, followed by centrifugation at 33,000 rpm to remove insoluble material and adjusted to 500 µg of protein/ml in PBS. The preparation was incubated with 1 µg/ml of trypsin/chymotrypsin at 37°C for 24 h, boiled for 5 min, and cooled on ice for 5 min. This was followed by digestions under identical conditions with papain (1 µg/ml) and finally proteinase K (1 µg/ml). The treated sonicates were extensively dialyzed in PBS before use in lymphocyte cultures. All proteases were purchased from Sigma (St. Louis, MO).
Organic M. tuberculosis extraction. Total sonicates of M. tuberculosis in PBS (10 mg dry weight bacteria/ml) were extracted (4:1 (v/v) organic to aqueous) with chloroform/methanol (2:1 (v/v)) after the method of Folch et al. (19). After phase separation, fractions were dried by rotary evaporation (organic phase) or lyophilized (aqueous phase and interface) and resuspended in the same starting volume (i.e., before extraction) in either chloroform (organic phase) or PBS (interface and aqueous phase). For in vitro assays, the organic phase was dried under nitrogen, resuspended in complete medium containing 10% FCS by water bath sonication for 5 min, and used at the desired concentrations.
Saponification. Organic M. tuberculosis extract equivalent to 2 mg of dry bacteria was dried under nitrogen, resuspended in 2 ml of 25% potassium hydroxide in chloroform/methanol (1:1), and autoclaved for 1 h at 121°C. After cooling, 2 ml of chloroform was added, followed by 1.5 ml of concentrated hydrochloric acid in water (1:1). The bottom layer was removed and dried, and insoluble salts were precipitated by adding 2% potassium bicarbonate in methanol/water (1:1), followed by chloroform. The supernatant containing free acyl chains was used for in vitro assays.
Silica column chromatography. Silica gel chromatography employing two different types of step gradients was used initially to separate the organic extract into broad lipid classes and then, subsequently, to refine the purification of the polar lipid fraction. For lipid class separations, a column was prepared with 1 g of silica gel (Selecto Scientific, Norcross, GA) and washed with chloroform. Organic extract equivalent to 10 mg dry M. tuberculosis was loaded onto the column in 0.2 ml of chloroform, and neutral lipid, glycolipid, and phospholipid fractions were eluted with 10 ml of chloroform, acetone, and methanol, respectively. To further define the active lipid component, an identical extract was eluted initially with chloroform and then, in a stepwise fashion, with mixtures of chloroform/methanol increasing in methanol proportion from 10 to 100% methanol.
TLC separations. Lipid fractions equivalent to 5 mg of dry bacteria obtained from step gradient silica column separation were loaded longitudinally on silica TLC plates (Scientific Adsorbents, Atlanta, GA), and the lipids were separated using chloroform/methanol/water (60:35:8 (v/v/v)). The bands containing lipids were localized after spraying the silica plates with water and were scraped off the glass. The silica was reduced to powder, and the lipids were re-extracted with chloroform/methanol for further use.
Cytokine release assays
Cytokine release from CD8-1 and CD8-2 (1 x 106
cells/ml) was measured by ELISA after stimulation with CD1+
monocytes (1 x 106 cells/ml) in a total volume of 1
ml with a 1:1500 dilution of M. tuberculosis organic extract
(10 mg/ml dry weight extract) or media for 24 h. IFN-
(Life
Technologies, Gaithersburg, MD), IL-4 (Genzyme, Cambridge, MA), and
TNF- (Endogen, Woburn, MA) ELISAs were performed according to the
manufacturers’ instructions.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß+ CD8+
T cell lines, purified CD8+ T cells from the blood of
healthy donors were cultivated in the presence of monocytes treated
with GM-CSF and IL-4 to induce expression of CD1a, -b, and -c molecules
(CD1+ monocytes, 1 and pulsed with an organic
extract of M. tuberculosis (containing mainly bacterial
lipids) as previously described (2). After three stimulations using
autologous monocytes as APCs, subsequent stimulations were conducted
with APCs from random donors to favor presentation of Ags by
nonpolymorphic molecules such as CD1. Two cell lines were obtained,
designated CD8-1 and CD8-2, and subjected to detailed study.
FACS analysis confirmed that these cell lines were TCR
ß+, CD8+, CD8ß+, but
CD28- (Fig. 1
).
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A). The restriction to CD1
molecules for CD8-1 cells was shown as monoclonal anti-CD1c mAb
blocked the Ag-specific proliferation by 100%, whereas CD1a, CD1b,
pan-MHC class I, or pan-MHC class II mAbs had no detectable effect. In
contrast to the effect of anti-CD1c mAb on the CD8-1 cell line,
only CD1a-specific mAb blocked proliferation of the CD8-2 T cell line
(Fig. 2A).
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B). In contrast, CD8-2 CTL recognized only Ag-pulsed
C1R/CD1a targets (31.2% specific lysis vs 4.6% for unpulsed target
cells). The CD8-2 cell line also showed weak reactivity against
Ag-pulsed C1R/CD1c (12.6%) vs unpulsed C1R/CD1c (4.7%), suggesting
that as an uncloned line, CD8-2 may contain predominantly
CD1a-restricted clones as well as some CD1c-restricted cells (Fig. 2B). Taken together, these data demonstrate the CD1a or -c
restriction of the TCR ß+ CD8+ T cell
lines CD8-2 and CD8-1, respectively, using both anti-CD1 mAb
blocking and CD1 transfectant analyses.
Next, we investigated the antigenic specificity among bacterial species
of the CD8-1 and CD8-2 T cell lines by assessing the stimulating
capacity of sonicates from different species of Gram-positive and
Gram-negative bacteria. CD8-1 and CD8-2 cells recognized M.
tuberculosis sonicates but did not recognize a variety of
nonmycobacterial species (e.g., 50,511 cpm for CD8-1 with M.
tuberculosis lysate vs 3,566 cpm with Escherichia coli
lysate; or 75,052 cpm for CD8-2 with M. tuberculosis vs
4,650 cpm with E. coli; Fig. 3). To identify the chemical nature of
the Ags recognized by these CD8+ T cell lines, the M.
tuberculosis sonicate was treated sequentially with several
broad-spectrum proteases, including trypsin/chymotrypsin, subtilisin,
and proteinase K. As predicted, a control mycobacteria-specific
CD4+ T cell line designated CD4-1, which is MHC
class II-restricted (data not shown), did not react to the
enzyme-treated M. tuberculosis lysate, due to proteolysis of
the class II presented protein Ags. In contrast, the dose response of
the two CD1-restricted T cell lines was not affected by these protease
treatments, suggesting that their Ags were of nonprotein nature (Fig. 4).
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). These data suggested that the CD8-1
Ag was distinct from the CD8-2 Ag.
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). This result suggested that the Ags
for the CD8+ T cell lines may contain acyl chains that were
covalently attached by base-labile ester linkage or other bonds
cleavable in 50% KOH.
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To examine the role of T cell surface accessory molecules in the
CD1-restricted Ag recognition, we used anti-CD4, anti-CD8,
or anti-CD8ß mAbs alone or in combination with anti-CD2 mAb
to inhibit cytotoxicity of CD8-1 and CD8-2 T cells against
CD1+ targets. Anti-CD8 or anti-CD8ß mAbs alone
failed to block killing. However, when a suboptimal concentration of
anti-CD2 mAb that only minimally blocked killing was used together
with anti-CD8 or anti-CD8ß mAbs, marked inhibition of
cytotoxicity was noted (Table I). For
example, for CD8-1 T cells, only 6% inhibition of killing was noted
with anti-CD2 mAb, while 24–38% blocking was seen when
anti-CD8 or anti-CD8ß mAbs were added (compared with 2%
when anti-CD4 mAb was added). For the CD8-2 cell line, 60–80%
inhibition was noted when anti-CD8 mAbs were combined with the
anti-CD2 mAb, compared with 26% blocking with anti-CD2 alone.
These results suggested that the CD8 and CD8ß glycoproteins were
likely to be involved in the cytotoxic process.
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(236 ng/ml
for CD8-1, 107 ng/ml for CD8-2; Table II)
and TNF- (0.61 ng/ml for CD8-1, 3.3 ng/ml for CD8-2) were found in
the supernatant of the cultures, whereas no Th2 cytokines (IL-4 (Table II) or IL-10 (data not shown)) were detected. Thus the CD8-1 and CD8-2
cell lines displayed a Th1-like cytokine pattern.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In humans, Mycobacterium leprae Ag-specific
CD8+ T cell lines have been derived from both healthy
individuals and leprosy patients (25). Such CD8+ T cells
have been assumed to be reactive to MHC class I molecules bound to
peptides that escape the bacteria-containing endocytic vesicles and
enter the class I pathway. Here, we show that CD8+ T cells
can also recognize microbial Ags in the context of CD1 molecules. The
CD1-restricted T cells are typically cytolytic like other
CD8+ T cells, and we have recently shown that they kill
infected monocytes (26) that may harbor tubercle bacilli. The
CD8+ CD1-restricted T cell lines produce Th1-type cytokines
and thus may also play a role in human tuberculosis similar to that
proposed for CD4+ T cells. IFN- produced upon
recognition of Ag by the CD8+ lymphocytes could activate
surrounding infected macrophages and induce infected cells to destroy
mycobacteria. Moreover, given the cytotoxic ability of CD8+
T cells, they may also play an important role in the direct killing of
mycobacteria-infected cells, releasing bacteria from this protected
environment so that other host effector cells or Abs can mediate their
destruction. Thus, recognition of infected macrophages by these
CD1-restricted CD8+ T cells may play an important role in
clearing intracellular microbial infections.
Here, two different CD1 molecules, CD1a and CD1c, were shown to present Ags to CD8+ T lymphocytes. One of these molecules, CD1c, has been demonstrated to be localized within endosomal compartments (M. Sugita and S. A. Porcelli, unpublished observation). In contrast, CD1a is thought to have a different trafficking route since it lacks the tyrosine-based motif present in the cytoplasmic tail of CD1b and -c (3). This raises the possibility that, similar to what was found for the MHC class I and II molecules, different CD1 isoforms may bind Ags encountered in different subcellular compartments. Since MHC class II-mediated presentation of peptides may be inefficient or inhibited in certain instances of M. tuberculosis infection of monocytes, CD1 may provide a crucial alternative route for foreign Ag presentation to T cells.
Our experiments indicate that the Ags recognized by CD1-restricted
CD8+ ß+ T cell lines are nonprotein in
nature. The Ags were resistant to broadly-reactive proteases and could
be isolated with organic extraction protocols that preferentially
isolate lipids. The Ags for both CD8-1 and CD8-2 T cell lines were
found in a concentrate of polar lipids extracted from M.
tuberculosis after separation by silica chromatography. Loss of
biological activity occurred after saponification. These results are
similar to those reported for other CD1-restricted T cells, where
mycolic acids and lipoarabinomannan were identified as Ags recognized
by CD1-restricted DN T cells (2, 4, 17). These data support the
hypothesis that CD1a, -b, and -c molecules are specialized in
presenting lipid and glycolipid Ags, which are chemically different
from the peptides that bind to MHC I and MHC II. Such reactivity would
greatly increase the universe of foreign Ags able to stimulate T cells
in bacterial infections and augment the diversity of the T cells that
participate in the immune response.
The structural similarities between the MHC I molecules and the CD1
glycoproteins have long been known. They are both composed of a
glycoprotein heavy chain with three extracellular domains, 1, 2,
and 3, non-covalently associated with ß2m (3). The
3 domain is Ig-like and bears significant amino acid similarities to
the corresponding domain of class I molecules. The CD8 blocking
experiments suggest that, as for MHC I-restricted T cells, the CD8
and CD8ß molecules (of CD1-restricted CD8+ T lymphocytes)
are involved in the recognition/activation mechanism. The involvement
of the CD8 glycoprotein in the recognition of the CD1 molecules is
further substantiated by experiments in the murine models. Hydrophobic
peptides presented by molecules related to human CD1d (mCD1.1 and
mCD1.2) have been suggested to be recognized by a subclass of
CD8+ T cells (27).
Given the characteristics of CD1 Ag presentation, including access to immunogenic nonprotein microbial cell wall Ags with the activation of distinct CD8+ T cell populations, the CD1 system is poised to play an important role in the host response to microbial infection.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Michael B. Brenner, Brigham & Women’s Hospital, Smith Building Room 552, 75 Francis Street, Boston, MA 02115. E-mail address:
3 Abbreviations used in this paper: ß2m, ß2-microglobulin; DN, CD4-CD8- double negative; GM-CSF, granulocyte-macrophage CSF.
Received for publication April 14, 1998. Accepted for publication September 9, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß+ T cells. Nature 372:691.[Medline]
T
cells. 1991. Eur. J. Immunol. 21:2999.
2/V2 subset in human mycobacteria-responsive T cell suggest germline gene encoded recognition. J. Immunol. 147:3360.[Abstract]
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