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24JQ T Cells: A Feedback Mechanism for Immune Regulation1
*
Division of Infectious Diseases, University of California Medical Center, Los Angeles, CA 90095;
AIDS Research Center/Infectious Disease Unit, Massachusetts General Hospital-East, Charlestown, MA 02129;
Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115;
§
Genetics Institute, Cambridge, MA 02140;
¶
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138; and
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Department of Pathology, Johns Hopkins University, Baltimore, MD 21287
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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24JQ) T cells are not well defined,
although production of IL-4 has been suggested as important for priming
Th2 responses. However, activation of human V24JQ T cell clones
by anti-CD3 resulted in the secretion of multiple cytokines notably
important for the recruitment and differentiation of myeloid dendritic
cells. Specific activation of V24JQ T cells was CD1d restricted.
Expression of CD1d was found on monocyte-derived dendritic cells in
vitro, and immunohistochemical staining directly revealed CD1d
preferentially expressed on dendritic cells in the paracortical T cell
zones of lymph nodes. Moreover, myeloid dendritic cells both activated
V24JQ T cells and were susceptible to lysis by these same
regulatory T cells. Because myeloid dendritic cells are a major source
of IL-12 and control Th1 cell differentiation, their elimination by
lysis is a mechanism for limiting the generation of Th1 cells and thus
regulating Th1/Th2 responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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24JQ T cells are believed to regulate Th1/Th2 immune responses,
but the mechanism has remained enigmatic. V24JQ T cells and their
murine homologues, the CD161+
V14J281+ T cells, are activated
specifically by the nonpolymorphic class Ib molecule CD1d
(1) through presentation of a glycolipid Ag
(2, 3, 4). Murine NK T cells were first reported to play an
important role in initiating Th2 responses through the burst production
of IL-4 on activation (5). Moreover, increasing the number
of NK T cells in nonobese diabetic mice by adoptive transfer or
transgenic expression of the V14J281 TCR protected these animals
from diabetes in an IL-4-dependent fashion (6, 7, 8). In
humans the presence of fewer V24JQ T cells and the complete loss
of IL-4 secretion by these cells also correlated with the development
of type 1 diabetes mellitus (9). However, studies of IL-4R
-chain knockout mice as well as studies in nonobese diabetic mice
suggested that many of the immunomodulatory effects of these cells are
not mediated by IL-4 (10, 11).
A direct requirement for the CD1d-restricted T cells in the generation
of Th2 responses was excluded by the observation that mice whose CD1d
locus was ablated by gene targeting retained the capacity to generate
Ag-specific Th2 responses (12, 13). In addition,
CD1d-restricted T cells were shown to be 1) required for the Th1-like
response of granuloma formation, 2) the source of T cell help and
IFN-
required for CD8+ CTL activation in
murine toxoplasmosis, 3) important for the maintenance of the gravid
state, and 4) critical for the generation of anterior
chamber-associated immune deviation (14, 15, 16, 17, 18).
V14J281 T cells were also shown to play a critical role in tumor
surveillance (19, 20, 21). In both V14J281 knockout and
Ab-mediated depletion models, these cells were shown to be required for
IL-12-mediated rejection of tumors. This function was markedly
augmented by the addition of a potent activating lipid Ag presented by
CD1d, -galactosylcerceramide
(-GalCer).5 The
immunopotentiating effect of -GalCer was the direct result of an
interaction of NK T cells with dendritic cells (DC) and required the
secretion of IL-12 by DC (22, 23).
The identity of natural CD1d-expressing target cells that trigger human
V24JQ T cells in vivo, however, remains a central question. The
tissue distribution of CD1d in humans has not been fully defined and
appears to be more limited than that found in mice (24, 25). Activation of human CD1d-restricted V24JQ T cells
induced the expression of the genes for several cytokines, chemokines,
and other T cell effector proteins critical for DC maturation, as
determined by transcriptional profiling (26). The key role
of myeloid DC in priming Th1 cellular immune responses
(27) raises the possibility that V24JQ T cells exert
their immunomodulatory effects through interaction with these cells. To
test this hypothesis, the expression patterns for CD1d found on DC in
vivo and in vitro were assessed, and the functional consequences of an
interaction between V24JQ T cell clones and DC cells were
examined.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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24JQ T cell clones
Derivation of V24JQ T cell clones has been previously
described (9). Briefly, PBMC from normal donors were
single-cell sorted for V24/Vß11 double-positive cells, which were
then grown with irradiated feeder PBMC (50,000 cells/well), irradiated
721.221 lymphoblastoid cells (5000 cells/well), PHA-P (1 µg/ml), IL-2
(10 U/ml), and IL-7 (10 U/ml) in RPMI 1640 (Sigma) containing 10%
heat-inactivated FBS, 2 mM L-glutamine, 10 mM HEPES, 100
U/ml penicillin, and 10 µg/ml streptomycin (R10). The resultant
clones were then propagated with periodic restimulation by anti-CD3
Ab in the presence of irradiated allogeneic feeder PBMC and
anti-CD3 Ab. Clones were confirmed to be positive for V24 and
NKR-P1A by flow cytometry and to have the V24JQ CDR3 TCR by
sequencing (data not shown).
Transcriptional profiling of T cells
Transcriptional analysis of V24JQ T cell clones was
performed using high density oligonucleotide arrays developed by
Affymetrix (San Jose, CA). Briefly, the cells were activated for 4
h with 10 µg/ml soluble anti-CD3 or control IgG, after which
total RNA was isolated and reverse transcribed. The resultant cDNA was
used for in vitro transcription with biotinylated nucleotides to
produce labeled antisense RNA, which was then hybridized to DNA
microarray chips (Genechips, Affymetrix). After staining with
PE-streptavidin, the fluorescence of bound RNA was quantitated using a
Genechip reader (modified confocal microscope).
Cytokine secretion and proliferation
V24JQ T cell clones were stimulated (25,000/well) with
plate-bound anti-CD3 or control isotype Ab for 4, 8, or 24 h.
Supernatants were collected and assayed for IL-4, IFN-, macrophage
inflammatory protein-1 (MIP-1), MIP-1-ß, TNF-, and GM-CSF by
quantitative ELISA (Quantikine kits, R&D Systems, Minneapolis, MN).
After 24 h, 1 µCi/well of [3H]thymidine
(DuPont-NEN, Boston, MA) was added, and incorporation was measured as
previously described (9). Restriction experiments using
CD1 isoforms (CD1a, CD1b, CD1c, CD1d, and pSR-neo vector alone) in
transfected C1R cells were also performed as previously described
(9, 28).
Preparation of myeloid DC
Monocyte-derived DC were generated from fresh PBMC using an adaptation of previously published methods (29) or were positively selected by anti-CD14 microsphere enrichment as described in the manufacturer’s protocols (Miltenyi Biotec, Auburn, CA). Briefly, freshly isolated PBMC prepared from allogeneic of sygeneic donors were enriched for monocytes by adherence and washing. Immediately after washing, the remaining monocytes were cultured in R10 supplemented with recombinant human IL-4 (Genzyme, Cambridge, MA) and recombinant human GM-CSF at 1000 U/ml each for an additional 7 days, yielding a nonadherent population of cells that were at least 90% CD1a+/DR+/CD3-/CD14- by flow cytometric analysis (not shown).
Cytolytic assays
Cytolytic activity by V24JQ T cell clones was determined
by measuring the specific release of 51Cr at
4 h. Target cells were labeled with 50 µCi of
Na251Cr (New England Nuclear,
North Billerica, MA) for 1 h and were washed twice. Cytolytic
activity was determined in standard chromium release assays with
U-bottom 96-well microtiter plates containing 104
labeled target cells/well, with the indicated ratios of effector cells.
After a 4-h incubation at 37°C, the supernatants were harvested and
counted on a gamma counter (Cobra, Packard, Downers Grove IL). The
percent specific lysis was calculated as [(experimental release
- spontaneous release)/(maximal release - spontaneous release)]
x 100. For some experiments cytolysis was tested under conditions of
calcium chelation in the presence of EGTA and
MgCl2, each at 4 mM.
Antibodies
The 42.1 anti-CD1d mAb was a gift from Dr. Steven Porcelli
(Brigham and Women’s Hospital). F(ab')2 of 42.1
and IgG1 control Abs were prepared with an Immunopure
F(ab')2 kit (Pierce, Rockford, IL). Goat
F(ab')2 anti-mouse IgG-FITC (human adsorbed)
was obtained from Caltag (Burlingame, CA). FcR-blocking reagent human
IgG was obtained from Miltenyi Biotec. NOR3.2 was obtained from
BioSource (Camarillo, CA). Anti-V24, -Vß11, -ßTCR, and -CD83
were obtained from Immunotech (Coulter/Beckman, Fullerton, CA).
Anti-CD1a, -CD4, -CD8, -CD40 ligand (CD40L), -CD80, -CD86, and HLA-DR
were obtained from PharMingen (San Diego, CA). Anti-CD3, clone UCHT1,
was obtained from Ancell (Bayport, MN), and IgG1 control was obtained
from Sigma (St. Louis, MO).
Flow cytometry
Stained cells were analyzed on a FACScan cytometer (Becton Dickinson, Franklin Lakes, NJ), and single-cell sorting was performed using a MoFlo cytometer (Cytomation, Fort Collins, NJ). For CD1d expression of CD40L, T cell clones were activated with PMA and ionomycin as previously described (9, 30).
Western blot analysis for CD1d
Immunoprecipitates of CD1d from lysates of 5 x 105 C1R/CD1d cells, 4 x 107 DC, and 4 x 107 control C1R/neo cells were prepared using mAb 42.1 coupled to protein A beads. The immunoprecipitates were resolved by SDS-PAGE (5–15%), and probed with an affinity-purified rabbit anti-CD1d polyclonal Ab (31). Bands were visualized by chemiluminescence.
Immunohistochemistry
The NOR3.2 mAb was used to determine CD1d expression in fixed, paraffin-embedded tissue by immunoperoxidase staining (Vectastain ABC elite kit with visualization using NovaRed, Vector Laboratories, Burlingame, CA). Staining was performed according to the manufacturer’s specifications with NOR3.2 used at a 1/100 dilution. The specificity of the signal was confirmed by blocking experiments using a GST-CD1d fusion protein (a gift from Dr. Steven Balk, Beth Israel Deaconess Medical Center, Boston, MA) compared with the GST protein alone (data not shown).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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24JQ T cells by anti-CD3
treatment
A detailed analysis of the transcriptional profile of V24JQ
T cells was performed using high density oligonucleotide arrays.
Activation of clones derived from normal donors resulted in the
expression of numerous effector molecules believed to be important for
the recruitment and differentiation of myeloid DC (Fig. 1
, A and B). Among
these were 4 of 16 chemokines examined and included MIP-1 and
MIP-1ß, which are thought to recruit macrophages and immature DC in
vivo (32). Also produced were GM-CSF, IL-4, and TNF-,
cytokines involved in the differentiation and maturation of myeloid DC
and their subsequent maturation (27, 29, 33, 34).
Activation also induced the expression of 8 of 26 cytokines tested.
These cytokines as well as CD40 ligand (27, 35) and 4-1BB
(36, 37) were produced by each of the V24JQ T cell
clones examined (Figs. 1 and 2). In
addition, activated V24JQ T cells expressed enhanced levels of
perforin and granzyme B, proteins usually associated with classic
cytotoxic T cells (38). Thus, their immunomodulatory
functions might not be limited to cytokine release, but could involve
cytolytic activities as well.
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24JQ T cells by CD1d expression on target cells
To investigate V24JQ T cell/DC interactions in a completely
autologous system, a new set of clones was generated. These clones were
tested for CD1d-specific responses against a panel of lymphoblastoid
C1R cells transfected with various CD1 molecules. Cytokine release, as
shown for IL-4 and IFN-, and proliferation of these clones were
specifically restricted by CD1d (Fig. 2
A). Activation was
induced by CD1d but not by CD1a, CD1b, or CD1c, in agreement with
previously published results (28, 39). Additionally,
V24JQ T cell clones specifically lysed C1R cells expressing CD1d,
but not the other CD1 family molecules (Fig. 2B). Thus,
CD1d-restricted triggering of the invariant TCR activates the secretion
of cytokines and a concurrent cytolytic response, a situation similar
to that observed for cytotoxic T cells triggered by MHC class I and
peptide epitopes (38, 40).
CD1d is expressed on myeloid-lineage DC
The combination of cytokines and cytolytic proteins produced by
V24JQ T cell clones suggested an effector role beyond that of
simple Th2 priming by IL-4 secretion, as previously proposed
(5). Given these observations, immune regulation by
V24JQ T cells might involve interaction with myeloid DC, which
are important for the generation of Th1-like responses. Immature DC
were derived from peripheral blood monocytes differentiated in vitro
with IL-4 and GM-CSF and subsequently matured with monocyte-conditioned
medium (29). Peripheral blood monocytes are known to
express low levels of CD1d, which is promptly lost on culture in vitro
(24, 25). Analysis of mature myeloid DC (DC1) derived from
peripheral monocytes demonstrated the reacquisition of CD1d expression
on the cell surface (Fig. 3, A
and B), whereas activated B and T lymphocytes did not
express CD1d (data not shown) (25). Immunohistochemical
analysis confirmed that CD1d was preferentially expressed in vivo on DC
in the paracortical T cell zones of lymph nodes (Fig. 3, C–N). Immunostaining of serial sections confirmed that the
CD1d is expressed on DC that also express CD1a and S100 (24, 41). CD1d was not expressed by follicular DC or follicle tingle
body macrophages and was largely absent from sinus histiocytes, i.e.,
CD1d expression was targeted to T cell-dependent lymphoid regions.
While surveying other histiocytic/monocytic populations in other forms
of reactive lymph nodes processes, striking CD1d staining was found on
epithelioid histiocytes in both caseating granulomas of
Mycobacterium tuberculosis infections and other
nonmycobacterial granulomas (J. Seibel, R. Khetawat, S. B. Wilson, and
F. K. Racke, manuscript in preparation). Interestingly, murine
V14J281 T cells have been shown to be required for granuloma
formation after challenge with lipid extracts from M.
tuberculosis (14). In addition, several tumors that
closely resemble DC and may be their neoplastic counterparts, namely
Langerhans cell histiocytosis and interdigitating DC tumors, also
consistently express CD1d (J. Seibel, R. Khetawat, S. B. Wilson, and F.
K. Racke, manuscript in preparation). Thus, the expression of CD1d on
DC both in vitro and in vivo suggested their potential as a physiologic
target for V24JQ T cells.
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24JQ T cells
The ability of V24JQ T cells to interact with DC was
confirmed by testing several V24JQ T cell clones for cytolysis of
DC from multiple healthy donors of differing MHC haplotypes (Fig. 4, A and B). Both
allogeneic and autologous DC were lysed by the clones, indicating that
killing was neither MHC restricted nor alloreactive. Furthermore,
cytolysis was completely abrogated by calcium chelation and was
markedly inhibited by the anti-CD1d mAb 42.1 (Fig. 4C).
These data suggest that killing was mediated via the perforin/granzyme
pathway and required CD1d. Comparison of immature
(CD83-) vs mature (CD83+)
phenotype DC (27, 33) demonstrated no consistent
difference in recognition by V24JQ T cells (Fig. 4A
and data not shown). Activation of V24JQ T cells by DC also
resulted in the secretion of both IL-4 and IFN- (Fig. 4D). Thus, exposure of V24JQ T cells to DC expressing
CD1d triggered both cytolytic functions and cytokine release.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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14J281 transgenic mouse (42). In this animal,
CD4+ T cells exhibited a 10- to 100-fold increase
in the capacity to secrete IL-4 on stimulation and had elevated levels
of IgE. However, mice whose CD1d locus was ablated by gene targeting
retained the capacity to generate Ag-specific Th2 responses at both the
cellular and Ab levels (12, 13). An absolute requirement
for IL-4 priming of Th2 responses by the CD1d-restricted T cell
population was also called into question when it was found that these T
cells can support Th2 differentiation in an IL-4R-deficient mouse
(10). A large number of studies suggest a more complex
role for these regulatory T cells. CD1d-reactive T cells have been
shown to be critical for tumor surveillance, control of viral
infections, initiation of Ag-specific tolerance, maintenance of the
gravid state, and control of autoimmune disorders (6, 7, 17, 18, 19).
To further understand the function of V24JQ T cells, individual
clones were examined by transcriptional profiling using high density
oligonucleotide arrays. After activation by anti-CD3, this family
of T cells was capable of secreting a broad panel of cytokines,
chemokines, and costimulatory proteins important for the recruitment
and differentiation of myeloid DC, including IL-4 and GM-CSF. Myeloid
DC cultured in the presence of these gene products expressed CD1d and
became specific targets for CD1d-restricted killing by V24JQ T
cells. Furthermore, CD1d was preferentially expressed on myeloid DC in
the paracortical T cell zones of lymph nodes, corroborating the in
vitro expression data. These results were consistent with the recent
report by Nicol et al. showing that myeloid DC expressed CD1d in vitro
and were targets for lysis by V24JQ T cell lines
(43).
Because human myeloid-derived DC (DC1) and lymphoid-derived DC (DC2)
regulate CD4+ Th cell responses, the specific
lysis of DC1 cells by V24JQ T cells suggests that their
immunomodulatory function is not limited to Th2 bias induced by IL-4
secretion (44, 45, 46). When cocultured with T cells, DC1
cells secreted high levels of IL-12 and induced T cells with a Th1
phenotype. Coculture with DC2 cells induced a marked Th2 response
(45). Thus, the specific lysis of myeloid DC (DC1) by
V24JQ T cells may serve as a negative feedback mechanism for
limiting Th1 T cell responses (Fig. 5).
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24JQ T
cells. In addition, the in vivo activation of CD1d-restricted T cells
by -GalCer treatment resulted in the marked activation of murine NK
cells (51). While this mechanism for activation of NK
cells may play a role in the regulation of DC in vivo, the direct
interaction between Cd1d-reactive T cells and DCs demonstrated here
would make this step unnecessary.
The site of interaction between V24JQ T cells and DC is presently
unknown. The paucity of V24JQ T cells in a typical lymph node
suggests that it may occur extranodally and that the CD1d-positive DC
present within the lymph node may be those that escape peripheral
destruction (5, 24). Regardless, the parallel tissue
distributions of V24JQ T cells within the reticuloendothelial
system and the in vivo expression pattern of CD1d (see Fig. 3) are
strong circumstantial evidence for a key role for their interaction in
regulating the generation of cellular immune responses. The
CD1d-restricted T cells are distributed in the liver, gut, spleen,
lymph nodes, and thymus (5, 24), sites of active Ag
sampling and presentation by professional APCs. Interestingly,
unregulated DC have also been shown to be capable of initiating and
maintaining autoimmunity by the presentation of tissue-specific
self-Ags (52, 53). Moreover, DCs lingered in the T cell
zones of lymph nodes as a result of missense mutations in the caspase
10 gene of patients with autoimmune lymphoproliferative syndrome type
II, a primary finding in this autoimmune disorder (54).
Dysfunction of CD1d-restricted T cells has been clearly correlated with
the development of T cell-mediated autoimmune diseases in both rodents
and humans (9, 11, 55, 56, 57). Furthermore, activation or
direct transfer of CD1d-restricted T cells was shown to directly
inhibit the development autoimmunity in these murine models of
autoimmunity (8, 11).
In summary, the present data suggest that V24JQ T cells are
activated by CD1d on myleloid DC (DC1) to secrete chemokines and
cytokines important for the recruitment and differentiation of DC and
thus play an important role in modulating DC function. This interaction
also activates the cytolytic functions of V24JQ T cells,
resulting in negative regulation of Th1 cellular immune responses
through cytolysis of DC. This system may be reciprocal to the negative
regulation of lymphoid DC (DC2) by mature T cells, which serves to
limit Th2 cellular responses (45).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Otto O. Yang, Division of Infectious Diseases, 37-121 CHS, University of California, Los Angeles Medical Center, 10833 LeConte Avenue, Los Angeles, CA 90095.
3 Address correspondence and reprint requests to Dr. Frederick K. Racke, AIDS Research Center/Infectious Disease Unit, Room 5234, Massachusetts General Hospital-East 149, 13th Street, Charlestown, MA 02129.
4 Address correspondence and reprint requests to Dr. S. Brian Wilson, Cancer Immunology and AIDS, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.
5 Abbreviations used in this paper: -GalCer, -galactosylcerceramide; DC, dendritic cell; CD40L, CD40 ligand; MIP-1, macrophage inflammatory protein-1.
Received for publication March 21, 2000. Accepted for publication July 10, 2000.
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References |
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/ß-T cell receptor (TCR)+CD4-CD8- (NKT) thymocytes prevent insulin-dependent diabetes mellitus in nonobese diabetic (NOD)/Lt mice by the influence of interleukin (IL)-4 and/or IL-10. J. Exp. Med. 187:1047.24JQ T cells in type 1 diabetes. Nature 391:177.[Medline]
secretion of peripheral natural killer T cells in nonobese diabetic mice suggests new pathogenic mechanisms for insulin-dependent diabetes. J. Exp. Med. 190:963. dependent immunity to Toxoplasma gondii in MHC class I-deficient mice. J. Exp. Med. 178:1465.14 NKT cells in abortion. Proc. Natl. Acad. Sci. USA 97:740.14 NKT cells in IL-12-mediated rejection of tumors. Science 278:1623.-galactosylceramide. J. Immunol. 163:2387.-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J. Exp. Med. 189:1121.14+CD4+NKT cells: atimulation of IL-12 production by antigen-presenting cells in the innate immune system. J. Immunol. 163:93.24JQ T cells from identical twins discordant for type I diabetes. Proc. Natl. Acad. Sci. USA 97:7411.24+ CD4-CD8- T cells. J. Exp. Med. 186:1.
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L. S. Metelitsa, O. V. Naidenko, A. Kant, H.-W. Wu, M. J. Loza, B. Perussia, M. Kronenberg, and R. C. Seeger Human NKT Cells Mediate Antitumor Cytotoxicity Directly by Recognizing Target Cell CD1d with Bound Ligand or Indirectly by Producing IL-2 to Activate NK Cells J. Immunol., September 15, 2001; 167(6): 3114 - 3122. [Abstract] [Full Text] [PDF]
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, Numbers of copies of
specific mRNA per million after treatment with IgG1 control; •, their
corresponding copy numbers after activation with anti-CD3
treatment. B, Cytokine release. Supernatants from
several V
