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,
*
Division of Dermatology,
Department of Microbiology and Immunology, and
Molecular Biology Institute, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095;
§
Service de Dermatologie, Hopital Edouard Herriot, Lyon, France;
¶
Department of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA 02115;
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RMF Dictagene S.A., Lausanne, Switzerland;
#
Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, FL 33101; and
**
Section of Dermatology and University of Southern California School of Medicine, Los Angeles, CA 90033
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and
GM-CSF, the Th1 pattern of cytokines required for cell-mediated
immunity against intracellular pathogens, but no detectable IL-4. The
existence of CD4+ CD1-restricted T cells that produce a Th1
cytokine pattern suggests a contributory role in immunity to
mycobacterial infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The CD1 proteins have been classified into two subgroups based on sequence similarity: The group 1 proteins which include human CD1a, CD1b, and CD1c molecules are much more closely related to one another than they are to the fourth human protein, CD1d. Group 2 proteins include human CD1d and murine CD1. Most of our knowledge about group 1 CD1-restricted T cells and their role in microbial infection derives from studies investigating the host response to mycobacteria. Immunity to mycobacterial infection requires both MHC class I- and class II-restricted T cells (7, 8) which are directed against peptide Ags. However, mycobacteria are characterized by a complex lipid and glycolipid envelope, which has potent immunostimulatory activity for B cells and monocytes (9, 10). Previous studies from our laboratories have shown that this complex mycobacterial lipid envelope is a rich source of CD1-restricted T cell Ags as well (4, 6, 11). The general structural features of these T cell Ags are a hydrophobic region (fatty acid chains) coupled to a polar or charged hydrophilic end. The large hydrophobic pockets identified in murine CD1 (12) are thought to be capable of accommodating the fatty acid portions of these Ags. Direct binding studies have confirmed that the lipid portion of CD1 ligands bind to CD1b (13).
As an initial step toward defining the in vivo relevance of CD1 Ag presentation, we have studied the involvement of CD1 in the immune response to Mycobacterium leprae, the causative agent of leprosy. Infection with this organism provides an opportunity to study the human immune response to a mycobacterial pathogen in situ, since much of the pathology is localized to the skin where the relevant lesions can be easily sampled. Furthermore, leprosy presents as a spectrum in which clinical disease correlates with different levels of responsiveness to M. leprae. At one pole of the spectrum are patients with strong cell-mediated immunity to M. leprae and a localized form of disease, which constitutes tuberculoid leprosy. At the opposite pole are patients with lepromatous leprosy, who lack effective cell-mediated immunity and suffer from a more disseminated form of the disease. The existence of this spectrum provides the opportunity to assess immunoregulatory mechanisms that may operate in vivo in humans to determine the ultimate outcome of the immune response to infection.
Previous studies have shown that only CD4-
(CD8+ and double negative
(DN))4 T cells
recognize mycobacterial Ags in the context of CD1 (4, 6, 14, 15). However, CD4+ T cells predominate in
the lesions of tuberculoid leprosy (16) and CD4 can be
expressed on group 2 CD1-restricted T cells (17). To
determine whether T cells expressing the CD4 coreceptor could be
selected by group 1 CD1 proteins, we derived CD4+
T cell lines from the lesions of leprosy patients. We identified three
CD4+ M. leprae-reactive,
CD1-restricted T cell lines: two that recognize mycobacterial Ags in
the context of CD1b and one that recognizes an as yet unidentified
lipid Ag in the context of CD1c. Monoclonal Abs that prevent
CD4+ HLA-DR-restricted T cells from responding to
Ag had no effect on CD4+ or DN CD1-restricted T
cells, indicating that the CD4 coreceptor does not impact positive or
negative selection of CD1-restricted T cells. The
CD4+, CD1-restricted T cell lines produced
IFN- and GM-CSF, the Th1 pattern of cytokines required for
cell-mediated immunity against intracellular pathogens, but no
detectable IL-4. Therefore, the existence of CD4+
CD1-restricted T cells that produce a Th1 cytokine pattern suggests a
contributory role in immunity to mycobacterial infection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Leprosy patients were recruited on a volunteer basis from the ambulatory population seen at the Dermatology Clinics at the University of Southern California Medical Center and the University of Miami Medical Center. Clinical classification of patients with symptomatic M. leprae infection was done according to the criteria of Ridley and Jopling (18). Skin biopsy specimens (6-mm diameter) containing both epidermis and dermis were obtained by standard punch technique following informed consent. Blood samples for isolation of PBMC were obtained by venipuncture from leprosy patients and from healthy volunteer laboratory personnel who served as control subjects and as a source for generating CD1+ APCs. PBMC were isolated using density gradient centrifugation (Ficoll-Paque; Pharmacia, Uppsala, Sweden).
Ags and Abs
Extracts of M. leprae, M. tuberculosis
(strain H37Rv), and M. phlei were prepared by probe
sonication (19). To prepare non-peptide Ags, sonicated
mycobacteria were treated with proteinase K (0.7 mg/ml, Boehringer
Mannheim, Indianapolis, IN) for 30 min at 60°C, and the enzyme was
heat-inactivated for 10 min at 70°C. Purified mycobacterial lipids
and lipoglycans were isolated as described previously (5, 11, 20, 21). The following Abs were used for flow cytometry: IgG
controls (Sigma, St. Louis, MO), OKT6 (anti-CD1a
(22)), BCD1b3.1 (anti-CD1b (23, 24)),
F10/21A3 (anti-CD1c (25)); OKT3 (anti-CD3;
American Type Culture Collection (ATCC), Manassas, VA); OKT4
(anti-CD4; ATCC); OKT8 (anti-CD8; ATCC), BMA 031
(anti-TCR
ß; Caltag, Burlingame, CA); 5A6.E9
(anti-TCR
; Caltag); HP-3D9 (anti-CD94; PharMingen, San
Diego, CA); DX12 (anti-CD161/NKR-P1A; PharMingen).
In vitro culture of CD1-expressing monocyte-derived dendritic cells
CD1 expression on monocytes was induced in vitro with a combination of recombinant human GM-CSF (200 U/ml) and recombinant human IL-4 (100 U/ml) for 72 h as described elsewhere (4, 4, 26, 27). Cells were harvested using incubation in PBS/0.5 mM EDTA to detach adherent cells and analyzed for CD1 expression by flow cytometry (4) or irradiated (5000 rad) and used as APCs.
T cell lines and proliferation assays
T cell lines were derived from leprosy lesions and the blood of
healthy donors as described previously (6, 28), although
CD4 and CD8 T cells were not depleted. Briefly, cells were extracted
from lesions with a tissue sieve and lymphocytes were isolated by
density gradient centrifugation. HLA-DR-restricted T cell lines were
initiated in the presence of irradiated autologous PBMC and
mycobacterial extract, whereas CD1-restricted T cells were cultured in
the presence of irradiated autologous CD1+ APCs
and extract (4). T cell lines were maintained by serial
antigenic stimulation in recombinant IL-2 (1 nM; Chiron Diagnostics,
Norwood, MA) supplemented medium. For measurement of Ag-specific
proliferation, T cells (1 x 104) were
cultured with varying numbers (usually 1 x
104) of irradiated (5000 rad) heterologous
CD1+ APCs in culture medium (0.2 ml) in the
presence or absence of bacterial Ags for 3 days in microtiter wells (in
triplicate) at 37°C in a 7% CO2 incubator.
Cells were pulsed with [3H]thymidine (1
µCi/well; ICN Biomedicals, Costa Mesa, CA) and harvested 4–6 h
later for liquid scintillation counting. To determine CD1 restriction
of the T cell lines, neutralizing CD1 Abs were added 30 min before the
addition of T cells. Alternatively, THP-1 cells expressing distinct
isoforms of CD1 were used as APCs (29). To determine the
role of CD4 accessory interactions, T cells were cultured with a
neutralizing CD4 Ab (clone QS4120; Calbiochem, San Diego, CA) or
isotype-matched control Ab for 30 min, cells were washed to remove
unbound Ab, and T cells were added to APCs and Ag. Cytokine release
from T cells was measured by ELISA after stimulation with CD1-positive
APCs and Ag or media for 24 h. ELISAs (IFN- and IL-4; Endogen,
Woburn, MA; GM-CSF, PharMingen, San Diego, CA) were performed according
to the instructions of the manufacturers.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We derived T cell lines from the granulomatous lesions of patients
with tuberculoid leprosy in the presence of CD1+
APCs and an extract of M. leprae. Flow cytometry and T cell
proliferative assays revealed that three cell lines (LCD4.1 (Fig. 1
), LCD4.2, and LCD4.3) from three
different patients expressed CD4 and TCRß and the ability to
respond to M. leprae Ag in the presence of heterologous
CD1+ APCs. These three cell lines were therefore
selected for further study.
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, a potent stimulus for MHC class II expression,
but no detectable IL-4 (Fig. 2). We have
previously shown that both GM-CSF and CD1 are elevated in tuberculoid
as compared with lepromatous lesions (32, 33). CD1
expression in vitro is dependent on cytokines, most notably GM-CSF
(4, 26). The CD4+ T cell lines also
produced GM-CSF in response to Ag. Together, these data suggest that
CD4 T cell lines stimulated under conditions to activate CD1-restricted
T cells produce cytokines that would enhance Ag presentation through
both the MHC class II and CD1 pathways.
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,
A and B, shows that Abs to CD1c blocked the
proliferation and IFN- production of the CD4+
T cell line LCD4.1, indicating that LCD4.1 recognized M.
leprae Ag in the context of CD1c. The CD1c restriction of LCD4.1
was confirmed using the monocytic cell line, THP-1, transfected with
distinct CD1 isoforms. CD1c-expressing THP-1 cells induced IFN-
production from LCD4.1 in the presence of M. leprae (Fig. 3C), whereas CD1b-transfected THP-1 did not induce IFN-
production. Similarly, LCD4.1 was activated to produce IFN- in the
presence of M. leprae-pulsed CD1c, but not CD1b-transfected
HeLa cells (data not shown).
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production of LCD4.2, indicating that
CD1b presented M. leprae Ag to LCD4.2 (Fig. 4, A and B).
Interestingly, THP-1 cells transfected with CD1a, CD1b, or CD1c did not
induce IFN- production from LCD4.2 (data not shown). The third
CD4+ T cell line, LCD4.3, produced IFN-, which
was inhibited by neutralizing Ab to CD1b, but not by anti-CD1a or
anti-CD1c (Fig. 4C), indicating CD1b restriction.
Finally, to demonstrate that this population of T cells was present in
the pool of peripheral blood T cells, we also derived CD1-restricted
CD4+ T cells from the blood of a healthy donor
(BCD4.1, Fig. 4D). We conclude therefore that
CD4+ T cells belong to the repertoire of T cells
that recognize microbial Ags in the context of group 1 CD1
proteins.
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Murine CD1-restricted T cells are characterized by their
expression of NK receptors, in particular NK1.1 (34), and
therefore are often referred to as NK T cells. Activation of NK T cells
through NK1.1 results in robust IFN- production (35) in
contrast to the large amounts of IL-4 produced after TCR stimulation
(36, 37), indicating distinct effector functions for NK T
cells depending on which receptor is stimulated. CD94 is a human NK
receptor (38) that has also been identified on
CD1d-restricted T cells (39). We evaluated the expression
of these NK receptors on CD1-restricted CD4+ T
cell lines derived from leprosy lesions. We found that NKR-P1A was
negative on both LCD4.1 and LCD4.3, whereas CD94 expression was
variable; LCD4.1 was CD94 negative and LCD4.3 was CD94 positive (Fig. 5). Additional cell lines must be
evaluated to gain a better understanding of the expression of NK
receptors on group 1 CD1-restricted T cells, but the lack of NKR-P1A
would appear to distinguish these T cells from NK T cells
(34, 39).
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To date, human CD1-restricted T cells have been shown to recognize
lipid and glycolipid Ags (5, 6, 11, 19), thus we
investigated the nature of the Ags that activated
CD4+ CD1-restricted T cells. LCD4.1 T cells were
activated by extracts from M. leprae, M.
tuberculosis, and M. phlei, (Fig. 6A), suggesting that the Ag
was structurally conserved in different mycobacterial species. To
determine whether the Ag was a protein, M. tuberculosis
extract was treated with proteinase K. Fig. 6B demonstrates
that proteinase K treatment of M. tuberculosis had no effect
on the ability to stimulate LCD4.1, whereas proteinase K abrogated the
ability of M. tuberculosis to activate an
HLA-DR-restricted T cell line LDR-2 (Fig. 6C), indicating
that LCD4.1 recognizes a non-peptide Ag. To determine whether the Ags
previously shown to stimulate CD1b- and CD1c-restricted T cells could
activate LCD4.1, lipoarabinomannan (LAM), glucose monomycolate (GMM),
and mycolic acids were added to T cell cultures. None of these three
CD1 ligands activated LCD4.1 (Fig. 6D). Our data indicate
that LCD4.1 recognizes a previously unidentified non-peptide
mycobacterial Ag in the context of human CD1c.
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A). LAM and phosphatidyl
inositol mannoside (PIM) induced IFN- production from LCD4.2,
whereas GMM and mycolic acids did not. We have previously identified
two CD1b-restricted
CD4-CD8- T cell lines
that recognize PIM and LAM (6, 40). To confirm that LCD4.2
recognized glycolipid Ag in the context of CD1b, we used neutralizing
Abs to CD1 molecules (Fig. 7B). Ab to CD1b inhibited IFN-
production from LCD4.2 by 82%, whereas anti-CD1c inhibition was
weak by comparison. As indicated above, THP-1 cells transfected with
CD1b did not stimulate LCD4.2, probably due to the requirement for the
mannose receptor for uptake of LAM and PIM for CD1b Ag presentation
(41). Taken together, with the data from Fig. 4
, we
conclude that T cell line LCD4.2 recognizes PIM in the context of
CD1b.
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C), a previously recognized CD1 Ag (5), but
exhibited no response to two other CD1b Ags, LAM (6) and
GMM (11). The data indicate that all three CD1-restricted
CD4+ T cell lines derived from leprosy lesions
recognized non-peptide Ags. Neutralization of CD4 on the cell surface does not inhibit CD4+ CD1-restricted T cells
The CD4 protein plays an important role in the interaction of
HLA-DR-restricted CD4+ T cells and their cognate
APCs both in the thymus and the periphery (42, 43, 44). We
examined whether neutralizing Abs for CD4 influence the response of
CD4+ CD1-restricted T cells to mycobacterial Ag.
CD4 Ab had minimal effect on the response of LCD4.1 or LCD4.3 to
M. leprae (Fig. 8,
A and B), whereas the Ab inhibited the
proliferation of an HLA-DR-restricted T cell line, D103-5 (45, 46), by 83% (Fig. 8C). These data indicate that the
CD4 accessory interaction between the T cell and APC is not required
for the response of CD4+ CD1-restricted T
cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß or TCRs (47). DN T
cells represent a minor subset of the T cell repertoire,
suggesting CD1-restricted T cells might play a minor role in immune
responses. However, recent studies indicate that human CD1-restricted T
cells can also express CD8ß heterodimers (14, 15).
The present study provides evidence that T cells expressing CD4 and
TCRß may recognize foreign Ags in the context of CD1 molecules.
Three CD4+ T cell lines were derived from leprosy
lesions that recognized non-peptide Ags in the context of CD1b or CD1c.
These T cell lines produced IFN- and GM-CSF, but no detectable IL-4,
and the response of the T cells did not require CD4 accessory
interaction, in contrast to a CD4+
HLA-DR-restricted T cell line. The existence of human
CD4+TCRß+ T cells that
are CD1 restricted suggests that the T cell response to Ag presented by
CD1 encompasses the complete repertoire of T cells. One unresolved question regarding CD1-restricted T cells is their representation in different subsets of the T cell repertoire. Our earlier studies demonstrated that CD1-restricted T cells can express CD8 or be CD4 and CD8 negative (DN) (4, 6, 14, 47). The present study now indicates that CD1-restricted T cells can express CD4+ coreceptors. Furthermore, both CD4+ and CD4- T cells have the capacity to recognize the same ligand (PIM) in the context of CD1b (6). In this study, we demonstrated that CD4 accessory interaction is not required for T cell recognition, thus one might conclude that CD4 has no contributory role to the ability of CD1-restricted T cells to recognize Ag or an inhibitory role in preventing such recognition. These findings, however, do not preclude that membrane reorganization and signaling of CD4 could occur in a normal fashion (48, 49, 50).
Our data may provide some insight into the role of coreceptors in selection of CD1-restricted T cells. Most of our understanding of selection of CD1-restricted T cells derives from studies in mice. CD1-restricted T cell selection does not require MHC class II molecules (17, 51) and although a role for MHC class I has not been ruled out, the ligand responsible is most likely CD1 itself (52). Since CD1-restricted T cells 1) can be CD4+ or DN (34), 2) can recognize the same glycolipid Ag regardless of CD4 expression (6), and 3) do not require CD4 accessory interactions, our findings indicate that MHC class II is not required for selection of human CD1-restricted T cells and that CD4 is not required for positive selection. The existence of CD4+ CD1-restricted T cells further suggests that CD4 does not negatively select against CD1 responses.
Using leprosy as a model of intracellular infection to evaluate the role of CD1 in human immune responses, we have derived CD4+ CD1-restricted T cells from lesions of patients with tuberculoid leprosy, those patients able to localize the infection and mount T cell responses against the pathogen. CD4+ T cells predominate in the lesions of tuberculoid patients (16) and CD4+ T cell clones derived from these lesions produce cytokines that promote cell-mediated immune responses (30). We have also found a strong correlation between the expression of three forms of CD1 (i.e., CD1a, CD1b, and CD1c) known to be involved in the presentation of mycobacterial lipid Ags and the presence of effective host immunity to M. leprae (33). CD1 expression in tuberculoid lesions was shown to be primarily restricted to a mature dendritic cell population, and in vitro functional studies revealed that dendritic cells bearing the phenotype found in tuberculoid lesions were strikingly efficient at presenting mycobacterial lipid Ags to CD1b-restricted T cells. Since all three group 1 CD1 proteins can present lipid Ags to T cells (5, 14, 19), these results support the hypothesis that lipid Ag presentation by the CD1 system plays a beneficial role in host immunity to microbial pathogens in vivo and that CD4+ CD1-restricted T cells participate in the local immune response.
Upon activation by mycobacterial Ag, CD4+
CD1-restricted T cells produced IFN- and GM-CSF similar to DN and
CD8+ T cells. IFN- is a critical cytokine for
immunity to mycobacterial infection as evidenced by the greater
susceptibility to infection in IFN- knockout mice and the greater
IFN- expression seen in tuberculoid leprosy (32, 53, 54). GM-CSF induces CD1 on monocytes, which would lead to a
greater frequency of Ag presentation to CD1-restricted T cells.
Together, our data suggest that CD1+ dendritic
cells at the site of disease present lipid Ags to
CD4+ T cells, leading to the Th1 cytokine
response and increased CD1 expression. In this manner,
CD4+ CD1-restricted T cells can contribute to
cell-mediated immune responses for host defense against intracellular
pathogens. In summary, our findings extend the universe of
CD1-restricted T cell repertoire to include CD4+ TCRß
T cells and identifies these cells as part of the immune response that
combats infection.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Peter A. Sieling, UCLA Dermatology, 52-121 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095.
3 Current address: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461.
4 Abbreviations used in this paper: DN, double negative; LAM, lipoarabinomannan; GMM, glucose monomycolate; PIM, phosphatidyl inositol mannoside.
Received for publication October 27, 1999. Accepted for publication February 16, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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