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Departments of
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Medicine and
Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A growing number of accessory molecules have been identified that can
function in adhesion and/or costimulation. One of the first accessory
molecules identified was LFA-1 (
L/ß2 or
CD11a/CD18) (15). LFA-1 is a member of the integrin family, a large
family of heterodimeric membrane glycoproteins that are involved in
both cell-cell and cell-matrix adhesions. The role of LFA-1 as an
adhesion molecule has been well described (16, 17). The interaction of
LFA-1 with its ligands allows for improved adhesion of leukocytes to
vascular endothelium, an essential step in the recruitment and
migration of leukocytes into inflamed tissue (18, 19, 20). Likewise,
LFA-1-mediated adhesion can facilitate Ag presentation to T cells, and
LFA-1 engagement has been reported to decrease the minimal stimulatory
dose of Ag by 10- to 100-fold (9, 10, 11, 12). In addition to the known role of
LFA-1 in T cell adhesion, there have been several reports that
implicate LFA-1 in costimulation of T cells. Early reports showed that
coengagement of LFA-1 with purified plate-bound ICAM-1 could enhance T
cell activation following cross-linking the TCR/CD3 complex (21, 22, 23).
In contrast, coimmobilization of anti-CD3 and another adhesion
molecule, ELAM-1, did not enhance T cell activation, indicating that
LFA-1 did not function solely by adhesion (22, 23). Furthermore, LFA-1
engagement could also enhance T cell activation mediated through
pharmacological means with PMA and ionomycin, where any adhesion
component of LFA-1 would be irrelevant (21). Collectively, these
studies indicated that LFA-1 could function as both an adhesion
molecule and a costimulatory molecule for T cell activation.
The potential costimulatory role for LFA-1 was questioned when it was compared with the potent costimulatory activity of CD28. In contrast to costimulation through CD28, coengagement of LFA-1 did not protect against the induction of T cell anergy (24, 25) and did not induce long term T cell survival (26, 27). In addition, costimulation through CD28 can occur at a site on the T cell separate from TCR signaling, indicating that CD28 can transduce independent signals from the TCR. In contrast, in most (9, 21, 27, 28), but not all (24, 29), studies the ability of LFA-1 to costimulate T cells required that the TCR and LFA-1 be engaged on the same surface of the T cell. Finally, although LFA-1 engagement can regulate T cell signaling and function, it has been difficult to identify proximal signals associated with LFA-1 triggering (10, 30, 31, 32). These findings raised the specter that LFA-1 was functioning primarily through T cell adhesion and enhancing TCR signaling, rather than transducing an independent costimulatory signal.
Recently, we and others have assessed the role of LFA-1 in T cell activation using APC that were generated by gene transfer of MHC and ICAM-1 into costimulation-negative cell lines (24, 27, 29, 33). In these studies it was found that Ag presentation by transfectants expressing MHC and ICAM-1 can induce IL-2 secretion and proliferation in naive T cells, whereas transfectants expressing only MHC cannot. Interestingly, the ability of LFA-1/ICAM-1 interactions to up-regulate IL-2 gene expression could also be detected in Th1 clones, although insufficient IL-2 was produced to induce T cell proliferation and protect against anergy induction (25, 27). Ag presentation by cells expressing MHC alone could functionally engage the TCR, inducing some, but not all, responses associated with T cell activation, indicated that LFA-1/ICAM-1 interactions were not required simply to form T cell:APC conjugates (27, 34). These results suggested that LFA-1/ICAM-1 interactions could transduce costimulatory signals. However, it remained possible that LFA-1-mediated adhesion was simply enhancing TCR engagement, and the apparent dependence on LFA-1 reflected a difference in the threshold of TCR signaling required to induce T cell proliferation (3, 35). To address this question, we increased the class II/peptide ligand density by transfection of class II covalently linked to antigenic peptide. These transfectants fail to induce naive CD4+ T cell proliferation despite their presentation of 10,000-fold more TCR ligand than is required to induce proliferation in the presence of LFA-1/ICAM-1 interactions. These results argue that coligation of TCR and LFA-1 can have a qualitative as well as a quantitative effect on T cell activation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A panel of transfectants in the fibrosarcoma cell line, 6132-PRO
(Pro), expressing I-Ad alone (ProAd), or in combination
with ICAM-1 (ProAd-ICAM) or B7-1 (ProAd-B7) has been previously
described (25, 27). The Pro cells were further transfected with cDNA
for Ad and for Aßd covalently bound to the
OVA peptide 323–339 (36) with and without ICAM-1 cDNA (9) to generate
ProAd/OVA and ProAd/OVA-ICAM cells. The T cell hybridoma cell lines
DO11.10 and 3DO54.8 (37) recognize a peptide fragment of OVA, 323–339,
in the context of MHC class II, I-Ad. All cell lines were
maintained in DMEM (Life Technologies, Gaithersburg, MD) supplemented
with 10% FCS, 2 mM glutamine, 0.1 mM nonessential amino acids, 40
µg/ml gentamicin, and 50 µM 2-ME. G418 (200 µg/ml) and/or 250
µg/ml xanthine, 15 µg/ml hypoxanthine, and 6 µg/ml mycophenolic
acid were added to the culture medium for maintenance of the
transfectants. In all experiments the adherent transfectants were
harvested with EDTA and gentle scraping, because the covalently
attached OVA peptide was sensitive to trypsin digestion.
CD4+ T cells were purified from lymph nodes of DO11.10 TCR
transgenic mice (38) by negative selection using a mixture of
anti-CD8 mAb (2.43) and anti-class II mAbs (M5/114, 25-9-17,
and 3JP) followed by lysis with rabbit complement (Accurate Chemical,
Westbury, NY) and removal of residual Ab-bound cells by incubation with
an equal number of sheep anti-mouse and sheep anti-rat
Ab-coated Dynabeads (Dynal, Oslo, Norway). The purity of
CD4+ T cells was confirmed by lack of proliferation to 2.5
µg/ml Con A (Sigma, St. Louis, MO) and by flow cytometry.
Flow cytometry
Expression of transfected molecules was determined by flow cytometry using the anti-class II mAb MKD6, the anti-ICAM-1 mAb YN-1.7.1, and the anti-B7-1 mAb 16-10A1. T cells were phenotyped with a biotinylated mAb, KJ1-26 (39), directed against the TCR clonotype expressed by DO11.10 T cells and with the fluorochrome-conjugated Abs, CD4, CD25, and CD69 (PharMingen, San Diego, CA). All other Abs were obtained from American Type Culture Collection (Manassas, VA) except 3JP and biotinylated KJ1-26, which were provided by Dr. Charlie Janeway (Yale University, New Haven, CT) and Dr. T. Barrett (Northwestern University, Chicago, IL), respectively.
T cell assays
For T cell proliferation of naive CD4+ T cells, 5.0 x 104 T cells were incubated with 5.0 x 104 mitomycin C (Sigma)-treated transfectants and various concentrations of Ag in a 96-well flat-bottom plate for 48 h. [3H]thymidine was added to the cultures for an additional 12–18 h before wells were harvested. The T cell hybridomas DO11.10 or 3DO54.8 (5.0 x 104) were cultured with 5.0 x 104 of each of the Pro panel transfectants and with increasing concentrations of Ag or with increasing concentrations of the anti-class II Ab M5/114. After 24 h, supernatants (at a final concentration of 3–33%) were assayed for the presence of IL-2 using the indicator cell line CTLL in a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT)3 assay (Sigma).
Immunoblots
Class II expression was determined by Western blotting as previously described (40), with 1 x 106 cell equivalents loaded per lane on a 10% SDS-PAGE gel. The blots were incubated with a 1/200 dilution of rabbit antisera directed against the cytosolic tail of I-Aß (41), followed by goat anti-rabbit horseradish peroxidase-conjugated Abs. Blots were washed extensively and developed with enhanced chemiluminescence (Amersham, Arlington Heights, IL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have previously assessed a functional role for LFA-1/ICAM-1 interactions in T cell activation by transfecting a costimulation-negative cell line (6132PRO) with class II alone (ProAd), with class II and ICAM-1 (ProAd-ICAM), or, as a positive control, with class II and B7-1 (ProAd-B7) (25). We have found that Ag presentation by ProAd-ICAM, but not ProAd, can induce IL-2 gene expression, but not proliferation, in Th1 clones and both IL-2 production and proliferation in naive CD4+ T cells (27). Although we could show that Ag presentation by ProAd does engage the TCR in Th1 clones, it was not clear whether the effect of ICAM-1 was quantitative, increasing the level of TCR stimulation through intercellular adhesion, or qualitative, changing the nature of T cell signaling through costimulation.
To address this issue we transfected the 6132PRO cells with a
covalently bound class II/peptide construct to increase the density of
TCR ligand. Pro cells were transfected with cDNA clones encoding
I-Ad molecules with the OVA peptide 323–339 covalently
coupled to the Aßd chain (36), either alone (ProAd/OVA)
or in combination with ICAM-1 (ProAd/OVA-ICAM). The expression of the
covalent Aßd protein was confirmed by immunoblot (Fig. 1
), demonstrating an appropriately slower
migrating band compared with that for cells expressing wild-type
Aßd. Equivalent levels of class II among the
transfectants was demonstrated by flow cytometry (Table I).
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, A and C).
Although the dose response appears to plateau near 2 µg/ml of
peptide, this reflects the limitation of the CTLL assay. Further
dilution of the supernatant (insets in Fig. 2, A and
C) revealed a linear dose response up to the maximum dose of
20 µg/ml without any evidence of a plateau. In contrast to ProAd,
ProAd/OVA can induce maximal IL-2 secretion from both hybridomas in the
absence of Ag (Fig. 2, A and C). To determine the
relative ligand density of class II/peptide ligand on ProAd/OVA and
ProAd at maximal Ag doses (20 µg/ml), T cell assays were performed in
the presence of increasing amounts of anti-class II Abs to inhibit
T cell activation (Fig. 2). The relative Ab concentration required for
50% inhibition should indicate the relative density of functionally
relevant TCR ligand on the two APC. We found that approximately
100-fold more anti-class II mAb was necessary to lower T cell
activation by the ProAd/OVA cell lines vs the ProAd cell transfectants.
Therefore, the covalent class II/peptide construct increases the
density of I-Ad/OVA complexes on the cell surface to
100-fold over that which can be loaded onto the ProAd cells at maximal
doses of exogenous peptide.
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In our previous studies we found that Ag presentation by
ProAd-ICAM could induce proliferation of naive CD4+ T
cells, whereas Ag presentation by ProAd cells could not (see Fig. 3) (27). However, it remained possible
that LFA-1-mediated adhesion was simply shifting the dose response of
Ag required for T cell activation by 100-fold, a level that could be
attributed to LFA-1-mediated adhesion (9, 10, 11, 12). To determine whether the
high level of TCR ligand expressed by ProAd/OVA would compensate for
this apparent requirement for LFA-1/ICAM-1 interactions, we assessed
the ability of ProAd/OVA to activate naive CD4+ T cells
(Fig. 3). Despite the high density of TCR ligand, ProAd/OVA does not
induce proliferation in naive CD4+ T cells. ProAd/OVA-ICAM
cells expressing similar levels of TCR ligand do induce naive T cell
proliferation, indicating that this large amount of Ag was not inducing
high dose suppression of T cell proliferation.
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). Addition
of 100-fold more Ag did not result in naive T cell proliferation when
presented by ProAd. Based on the results shown in Fig. 2, ProAd/OVA
cells present 100-fold more class II/peptide complexes than does ProAd
at the maximal dose of exogenous Ag (20 µg/ml). Taken
together, these results show that ProAd/OVA APC are presenting
10,000-fold more effective class II/OVA complexes compared with the
minimum level required to activate the naive CD4+ T cells
in the presence of the LFA-1/ICAM-1 interactions (Fig. 3B).
Despite this high concentration of TCR ligand, ProAd/OVA cells do not
induce naive T cell proliferation, indicating that the role of ICAM-1
is to modify the quality, rather than simply the quantity, of TCR
signaling. ProAd/OVA can effectively interact with naive T cells and initiate TCR signaling
One potential caveat to these studies is that in the absence of
intercellular adhesion, Ag presentation by ProAd or ProAd/OVA cells may
not effectively engage the TCR. We have shown that these cells do form
productive conjugates with Th1 clones (27), but the adhesion
requirements for naive T cell and T cell clones are different. To
determine whether ProAd and ProAd/OVA could interact with naive T cells
and initiate TCR signaling, we assayed the expression of CD69 and CD25
at 13 h after activation. These early activation markers can be
induced in the absence of fully effective T cell activation (2, 34) and
serve as a useful marker for initial TCR engagement. As can be seen in
Fig. 4, Ag presentation by ProAd and
ProAd/OVA can induce the expression of both these markers. The number
of T cells expressing these markers is higher following Ag presentation
by ProAd-ICAM and ProAd/OVA-ICAM, consistent with an increase in
effective conjugate formation in the presence of a potent adhesion
molecule (Fig. 4). This difference in the number of responding T cells
cannot account for the failure to detect [3H]thymidine
incorporation in T cells stimulated with ProAd and ProAd/OVA cells
observed in Fig. 3. As noted previously for CD8 T cells (2, 34), the
level of expression of these markers was also increased after
stimulation with the ICAM+ and B7+
transfectants (data not shown). Whether this reflects a change in the
nature or duration of T cell signaling is not clear. Nevertheless,
these results indicate that Ag presentation by ProAd and ProAd/OVA can
functionally engage the TCR, resulting in transcription and expression
of cell surface activation markers, but not T cell proliferation.
Costimulation is required to induce IL-2 expression and proliferation
in the DO11.10 T cells, and this costimulation can be mediated by both
CD28/B7-1 and LFA-1/ICAM-1 interactions.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this report we have used covalent class II/peptide complexes
to increase TCR ligand to higher concentrations than we can by loading
class II with exogenous peptide. We have found that the expression of
the covalent class II/peptide complex presents 100-fold more functional
TCR ligands that we can load with exogenous Ag, but these cells cannot
induce proliferation of naive CD4+ T cell isolated from
DO11.10 TCR transgenic mice. In contrast, these same T cells will
proliferate to 10,000-fold less TCR ligand in the presence of
LFA-1/ICAM-1 interactions. This is well beyond the 10- to 100-fold
increase in Ag sensitivity that has been attributed to LFA-1-mediated
adhesion (9, 11, 29, 48). The lack of T cell activation in this high
MHC/peptide density system is not secondary to an inability of the APC
and T cells to form conjugates and subsequently engage the TCR, because
Ag presentation by ProAd and ProAd/OVA did up-regulate the expression
of the T cell activation Ags, CD25 and CD69. In addition, in our
previous studies with Th1 clones, Ag presentation by ProAd clearly
engaged the TCR, as evidenced by the nuclear localization of NF-AT and
NF-
B, but costimulation through LFA-1 or CD28 was required for the
expression of detectable levels of IL-2 mRNA (27). Thus, taken together
these data suggest that LFA-1/ICAM-1 interactions can modify the
quality as well as the quantity of TCR signaling.
The failure of high concentrations of TCR ligand alone to induce proliferation in DO11.10 T cells is in agreement with a previous study showing that naive CD4+ T cells from 2B4 TCR transgenic mice would not respond to purified class II/peptide complexes in the absence of accessory cells (49). However, the opposite conclusion has been reached in an analysis of naive CD8+ T cells, where high concentrations of plate-bound class I/peptide complexes did induce proliferation in T cells from 2C TCR transgenic mice (50). This apparent discrepancy could reflect a difference in the requirement for activation between CD4+ and CD8+ T cell subpopulations (5, 7). Alternatively, these differences may reflect the inherent affinity or dissociation rates of the different TCR molecules for their ligands (51). The 2B4 and DO11.10 CD4+ T cell used in these studies have relatively low affinity (5 x 10-5 and 2 x 10-4 M, respectively), and the 2C CD8+ T cells have a relatively high affinity (1–5 x 10-7 M) for their respective ligands (52, 53, 54, 55). High affinity TCR molecules may remain ligand bound for sufficient time to recruit all the necessary signal transduction components required to induce T cell proliferation. In this case, although costimulation may not be required for T cell activation, it could lower the threshold of T cell signaling and may still be required for long term T cell survival (13, 14). In contrast, low affinity TCR molecules may not be able to complete the recruitment of the intracellular signaling apparatus necessary for T cell proliferation without the participation of costimulatory molecules. Intracellular signals mediated through coengaged costimulatory molecules would be integrated with those transduced by the low affinity TCR complexes to enhance T cell activation. Our data indicate that the DO11.10 TCR falls into the second class, where TCR engagement alone does not induce proliferation and demonstrates that coengagement of LFA-1 can mediate the necessary costimulatory signals for T cell proliferation.
We have considered two possible mechanisms that might account for the ability of LFA-1 to modify the quality of TCR signaling. First, LFA-1 itself might initiate a signaling pathway that, along with signals generated from the interaction of the TCR with its ligand, provides for T cell activation. There is ample evidence that integrins can transduce important biological signals, and this role has been well documented in nonlymphoid cells (for reviews, see 56, 57, 58, 59, 60). However, in T cells, LFA-1 engagement has not been clearly associated with a distinct intracellular signaling pathway. The best evidence is that coligation of LFA-1 and CD3 can lead to a sustained intracellular calcium response and increased inositol phospholipid hydrolysis (30, 32, 61). Whether these enhanced responses result from increased signals mediated through the TCR complex or independent signals transduced through LFA-1 and, if so, how these LFA-1-mediated signals are integrated with TCR signaling pathways have not been clearly established.
Second, LFA-1 may function in the structural organization of the adhesion complex between T cells and APC. It has recently been shown that LFA-1 segregates into the outer perimeter of the adhesion complex, focusing TCR and engaged MHC/peptide complexes into a small central subdomain of the cell:cell contact region (62). This focal concentration of TCR within the adhesion complex could facilitate serial engagement of the TCR on a limited number of MHC/peptide complexes. More interestingly, it may provide an increased relative concentration of engaged TCR molecules, allowing for more efficient lateral interactions that lead to ligand-induced multimerization of the TCR (63). This may be more important for TCR molecules that have a relatively fast off rate and may account for the association between LFA-1 dependence and TCR affinity as discussed above. As has been proposed for signaling through altered peptide ligands (51, 63), the level of TCR oligomerization could alter the magnitude and quality of TCR signaling. If LFA-1 contributes to the structure of the adhesion complex, then its apparent ability to costimulate T cells may not be through direct signaling, but rather by stabilizing TCR/peptide-MHC interactions or enhancing TCR oligomerization. In either case this could result in a change in the quality of TCR signaling, because it could allow for the recruitment of additional downstream signaling molecules to the TCR/CD3 complex. Other adhesion molecules that do not determine the ultimate structure of the adhesion complex would not mediate this same functional effect on T cell activation as does LFA-1.
A role for LFA-1/ICAM-1 interactions in establishing the structure of the adhesion complex has not been established. However, two features of LFA-1 make this possibility likely. The molecular size of LFA-1/ICAM-1 complex may cause it to segregate from the smaller TCR/MHC/peptide complex (64, 65, 66, 67). Sorting of plasma membrane proteins according to the molecular size could account for the apparent distribution of LFA-1 and TCR in the adhesion complex (62). Alternatively, the generation of this complex could be an active process mediated through reorganization of the cortical actin cytoskeleton. Integrin-mediated adhesion and function are intimately associated with the actin cytoskeleton, and LFA-1 is no exception (68, 69, 70, 71, 72, 73). Thus, LFA-1 may contribute to the structure of the adhesion complex by directing the reorganization of the cortical actin cytoskeleton. An intact actin cytoskeleton is required for T cell activation (1), but complete disruption of actin with cytochalasin D inhibits T cell:APC conjugates, so it has not yet been possible to assess a role for actin in the spatial organization of proteins within the adhesion complex. Regardless of the mechanism, the morphological data on the position of LFA-1 within the adhesion complex (62) and our functional data on the importance of LFA-1 in T cell activation indicate that the role of LFA-1 extends beyond providing the molecular adhesion to stabilize the T cell:APC conjugate and suggests that LFA-1 can also play an important role in modulating the quality of TCR signaling. These issues will become clearer as we further dissect the molecular organization and interplay of proteins within the adhesion complex between T cells and APC.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jim Miller, Department of Molecular Genetics and Cell Biology, University of Chicago, 920 E. 58th St., Chicago, IL 60637. E-mail address:
3 Abbreviation used in this paper: MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide.
Received for publication October 6, 1998. Accepted for publication January 14, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Lß2 integrin avidity in transendothelial chemotaxis of mononuclear cells. J. Immunol. 159:3968.[Abstract]
1 activation. Proc. Natl. Acad. Sci. USA 90:7099.L/ß2 leukocyte integrin (LFA-1) by cyclic AMP-dependent protein kinase. J. Immunol. 156:2273.[Abstract]
-actinin. J. Immunol. 151:3795.[Abstract]
Lß2 (LFA-1, CD11a/CD18) cytoplasmic domain/cytoskeleton interaction. J. Exp. Med. 181:315.Lß2 are involved in endoplasmic reticulum retention, dimerization, and cytoskeletal association. J. Immunol. 155:1252.[Abstract]
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