J. Exp. Med.,
Volume 189, Number 7, April 5, 1999 1025-1031
TRANCE, a Tumor Necrosis Factor Family Member Critical
for CD40 Ligand-independent T Helper Cell Activation
By
Martin F.
Bachmann,*
Brian R.
Wong,
Régis
Josien,§
Ralph M.
Steinman,§
Annette
Oxenius,
and
Yongwon
Choi¶
From the * Basel Institute for Immunology, CH 4005 Basel, Switzerland; the Institute for
Experimental Immunology, 8019 Zürich, Switzerland; and the § Laboratory of Cellular Physiology and
Immunology, the Laboratory of Immunology, and the ¶ Howard Hughes Medical Institute,
The Rockefeller University, New York 10021
 |
Abstract |
CD40 ligand (CD40L), a tumor necrosis factor (TNF) family member, plays a critical role in
antigen-specific T cell responses in vivo. CD40L expressed on activated CD4+ T cells stimulates antigen-presenting cells such as dendritic cells, resulting in the upregulation of costimulatory molecules and the production of various inflammatory cytokines required for CD4+ T cell
priming in vivo. However, CD40L- or CD40-deficient mice challenged with viruses mount
protective CD4+ T cell responses that produce normal levels of interferon 
, suggesting a
CD40L/CD40-independent mechanism of CD4+ T cell priming that to date has not been elucidated. Here we show that CD4+ T cell responses to viral infection were greatly diminished
in CD40-deficient mice by administration of a soluble form of TNF-related activation-induced
cytokine receptor (TRANCE-R) to inhibit the function of another TNF family member,
TRANCE. Thus, the TRANCE/TRANCE-R interaction provides costimulation required
for efficient CD4+ T cell priming during viral infection in the absence of CD40L/CD40. These results also indicate that not even the potent inflammatory microenvironment induced
by viral infections is sufficient to elicit efficient CD4+ T cell priming without proper costimulation provided by the TNF family (CD40L or TRANCE). Moreover, the data suggest that
TRANCE/TRANCE-R may be a novel and important target for immune intervention.
Key words:
TRANCE;
CD40 ligand;
T cell;
dendritic cell;
virus
| |
Introduction |
ATNF family member, CD40L, has been shown to be
critical for the generation of antigen-specific T cell
responses in vivo (1). CD40L expressed on activated
T cells triggers CD40 on macrophages and dendritic cells
(DCs),1 resulting in the upregulation of costimulatory molecules and the induction of IL-12 in these APCs (9).
These costimulatory molecules and IL-12 then potentiate
CD4+ T cell responses in vivo (1, 9, 10, 14). However, CD40L- or CD40-deficient mice challenged with
viral infections such as lymphocytic choriomeningitis virus
(LCMV) are able to mount protective CD4+ T cell responses that produce normal levels of IFN- (19). In
addition, a majority of CD40L-deficient patients with hyper-IgM syndrome (HIGM) do not show increased susceptibility to various infections associated with defective CD4+ T
cell immune responses (22), suggesting that some pathogens are able to activate CD4+ T cells via a CD40L/CD40-independent pathway. The mechanism determining CD40/
CD40L independence of CD4+ T cell responses during intracellular infections is not understood. It has been speculated
that destruction of infected cells and the production of various inflammatory cytokines (e.g., INF-) in response to, for
example, viral infections constitute a sufficiently powerful adjuvant effect to allow the activation of T cells in the absence
of costimulation provided by CD40L/CD40 interaction.
In this study, the cellular immune responses to viral infections were examined in order to elucidate the factor(s)
responsible for CD40L/CD40-independent CD4+ T cell
priming. We show here that CD40L/CD40-independent
activation of CD4+ T cells during viral infection requires
TRANCE/TRANCE-R interaction (23). Thus, this
study suggests that CD4+ T cell priming in general is likely
to be regulated by one of two TNF family members
(CD40L or TRANCE).
| |
Materials and Methods |
Mice, Viruses, Cells, Abs, and Recombinant Proteins.
CD40-deficient mice have been described and were originally provided by
Dr. H. Kikutani (Osaka University, Osaka, Japan [26]). As control mice, CD40+/
or C57BL/6 mice were used, giving similar
results. LCMV (WE strain) was grown on L cells at a low multiplicity of infection. LCMV WE was originally provided by Dr.
R. Zinkernagel (University of Zürich, Zürich, Switzerland). Influenza virus (strain PR8) was originally provided by Dr. J. Pavlovic
(University of Zürich) and grown in day 10-fertilized chicken
eggs. Mature bone marrow-derived DCs were generated as described (24). Anti-IL-12 p35 (C18.2) and p40 (C15.1) mAbs were
provided by G. Trinchieri (Wistar Institute, Philadelphia, PA [27]).
For activation of T cells in vitro, T cells were purified and stimulated with anti-CD3 and anti-CD28 Abs as described previously
(24). Soluble TRANCE produced from recombinant baculoviruses has been described previously (24). TRANCE-R-Fc
(TR-Fc), a recombinant protein of the extracellular domain of
TRANCE-R fused to the constant region of human IgG1, was
produced in a similar way using a baculovirus system and purified on protein A-Sepharose beads (Amersham Pharmacia Biotech).
Infection and Treatment with TR-Fc.
For LCMV-specific CD4+
T cell proliferation, mice were infected intravenously or into one
hind footpad with 200 PFU of LCMV WE. Spleen cells were
isolated 13 or 30 d later, and proliferation and cytokine production were measured as described (19). To assess cytotoxicity,
mice were infected intravenously with 200 PFU of LCMV, and
spleen cells were isolated 8 d later. For influenza virus-specific
proliferation, mice were infected intranasally with virus (0.1 hemagglutination U/mouse). Spleen cells were isolated 8 d later. Mice
were injected three times, on days 0, 2, and 5 after infection,
with 100 µg of either TR-Fc or control hIgG1.
CTL and B Cell Responses.
EL-4 target cells were pulsed
with peptide p33 (KAVYNFATM) at a concentration of 107 M
for 90 min at 37°C in the presence of [51Cr]sodium chromate in
IMDM supplemented with 10% FCS. Cells were washed three
times, and 104 cells were transferred to a well of a round-bottomed
96-well plate. Stimulated or ex vivo-isolated spleen cell suspensions were serially diluted and mixed with peptide-pulsed target
cells. Plates were centrifuged and incubated for various time
spans at 37°C. At the end of the assays, 70 µl of supernatant was
counted in a -counter. Spontaneous release was determined by
adding medium instead of effector cells, and total release was determined by adding 2 M HCl instead of effector cells. Percent
specific release was calculated as 100 × (experimental release 
spontaneous release)/(total release spontaneous release). For assessment of B cell responses, LCMV-specific IgG Abs were determined as described on plates coated with LCMV nucleoprotein
produced by recombinant baculoviruses (19). PNA staining was
performed on acetone-fixed frozen sections as described (28).
In Vitro Proliferation and Production of IFN-.
For LCMV-specific CD4+ T cell proliferation, spleen cells were isolated 13 or 30 d
after infection and CD4+ T cells were purified by MACS®
according to the instructions of the supplier (Miltenyi Biotech). Purity was >95%. 105 CD4+ T cells were stimulated with 105 irradiated LCMV (highest concentration = multiplicity of infection = 0.3) or peptide 13 (GLNGTDIYKGVYQFKSVEFD;
highest concentration = 3 µg/ml)-pulsed splenic APCs, and proliferation was assessed 3 d later by [3H]thymidine incorporation.
Production of IFN- was assessed in the wells with the highest
antigen concentration by ELISA (19). For influenza virus-specific
CD4+ T cell responses, spleen cells were isolated 8 d after infection, and purified CD4+ T cells (2 × 105 cells/well) were restimulated with irradiated spleen cells (105 cells/well) in the presence
of various concentrations of UV light-inactivated, purified influenza virus. Proliferation and IFN- production were measured as
described above.
| |
Results and Discussion |
A recently identified member of the TNF receptor family, TRANCE-R (also called RANK), has been shown to be
expressed at high levels on mature DCs (23). Moreover,
TRANCE treatment enhanced the survival of mature DCs,
indicating that TRANCE-R may exhibit a similar function
as CD40 on these cells (24). To test whether TRANCE/
TRANCE-R interaction may play a role in T cell activation, surface expression of TRANCE was analyzed on activated
T cells. Similar to CD40L, surface TRANCE expression was
highly upregulated on T cells upon stimulation through
antigen receptors (Fig. 1 A). Moreover, when mature DCs
were treated with soluble TRANCE, the expression of
IL-12 (Fig. 1 B) and other inflammatory cytokines (e.g.,
IL-1 or IL-6; data not shown) was induced in mature DCs, a property also shared by CD40L (11). Together, these
results suggested that TRANCE and CD40L may share
some similar functions in vivo during T cell activation and
that TRANCE may be responsible for CD40L-independent CD4+ T cell responses, as observed in some murine
model systems such as during viral infections (19).
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Fig. 1.
(A) TRANCE expression is upregulated after T cell activation. Purified T cells were stimulated with anti-CD3 plus anti-CD28 and
stained with TR-Fc or control hIgG1, followed by FITC-conjugated
goat anti-human IgG (Fc-specific) F(ab')2 fragment (Jackson ImmunoResearch Laboratories). (B) TRANCE induces IL-12 production in mature
DCs. Mature bone marrow-derived DCs were cultured for 18 h in the
presence or absence of soluble TRANCE (1 µg/ml), then fixed in 2%
PFA. After incubation in 0.5% saponin, the cells were stained with anti-
IL-12 p35 (C18.2), anti-IL-12 p40 (C15.1) (solid line), or control rat IgG
(dotted line) followed by anti-rat IgG-PE (Jackson ImmunoResearch
Laboratories), and analyzed by FACS®. In parallel experiments, soluble
CD40L also induced IL-12 p35 and IL-12 p40, at levels quantitatively
similar to those induced by soluble TRANCE (data not shown).
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To test this hypothesis, we chose to study the immune
response to LCMV infection as a murine model since it has
been extensively characterized and also because the activation of CD4+ T cells during LCMV infection was shown
not to be affected in CD40L- or CD40-deficient mice (19).
To analyze whether TRANCE is upregulated in vivo
during the course of an immune response after viral infection, mice were infected with LCMV, and spleen cells were
analyzed for TRANCE expression 8 d later. Indeed, the
proportion of TRANCE-expressing T cells increased after
infection (~6% of CD4+ T cells and ~7% of CD8+ T cells
became TRANCE-positive, whereas 0% of T cells expressed TRANCE in uninfected control mice).
To determine whether TRANCE plays a role during immune responses in vivo, and if so, whether it exhibits a compensatory role for CD40L during viral infections, we tested
the consequences of blocking the TRANCE/TRANCE-R
interaction by injection of TR-Fc on antigen-specific B,
CD8+, and CD4+ T cell responses induced by LCMV infection in control (C57BL/6 or CD40+/) and CD40-deficient mice (26).
The most prominent role of CD40L is to promote isotype switching in activated B cells and to allow the formation of germinal centers (GCs; 1-3). Indeed, CD40-deficient mice failed to produce high titers of LCMV-specific
IgG Abs and produced no GCs (Fig. 2, A, D, and E). In contrast, TR-Fc-treated C57BL/6 mice mounted LCMV-specific IgG responses comparable to those of control mice treated
with hIgG1 (Fig. 2 A) and generated similar numbers of GCs of normal architecture (Fig. 2, B and C). These results
suggest that the TRANCE/TRANCE-R interaction does
not play a critical role in T-B cell collaboration, despite the
low level of TRANCE-R that can be detected on activated B cells (data not shown).
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Fig. 2.
(A) Blocking TRANCE does not affect isotype switching after LCMV infection. C57BL/6 mice (triangles) or CD40-deficient mice (circles)
were infected with LCMV and treated with TR-Fc (filled symbols) or control hIgG1 (open symbols). LCMV-specific IgG Abs were assessed 14 d later
by ELISA. One representative experiment of two is shown. (B-E) Blocking TRANCE does not affect GC formation after LCMV infection. C57BL/6
mice (B and C) and CD40-deficient mice (D and E) were infected with LCMV and treated with either TR-Fc (B and D) or control hIgG1 (C and E).
The presence of GCs was assessed 14 d later in spleens by PNA staining. One representative experiment of two is shown.
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We next analyzed the ability of TR-Fc-treated control
and CD40-deficient mice to mount LCMV-specific T cell
responses. Mice were injected with LCMV, and CD8+
T cell-mediated responses were analyzed in a 51Cr-release
assay 8 d later (Fig. 3 A). In keeping with previous reports
(20, 21), the CD40L/CD40 interaction was not required for
efficient primary CTL responses against LCMV (Fig. 3 A). In addition, inhibition of the TRANCE/TRANCE-R interaction did not affect the LCMV-specific acute CTL responses
(Fig. 3 A). Moreover, inhibition of both the TRANCE/
TRANCE-R and CD40L/CD40 interactions did not affect
acute CTL responses (Fig. 3 A). These results suggest that primary LCMV-specific CTL responses are largely independent of CD40L and TRANCE on activated T cells.
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Fig. 3.
Blocking TRANCE does not
interfere with the induction of cytotoxic T
cells but plays a role in the LCMV-specific
CD4+ T cell responses. C57BL/6 mice (triangles) or CD40-deficient mice (circles)
were infected with LCMV and treated with
TR-Fc (filled symbols) or control hIgG1
(open symbols). (A) The presence of
LCMV-specific cytotoxic T cells was assessed 8 d after infection using peptide p33-
pulsed EL-4 cells as target cells. (B and C)
Spleen cells were isolated 13 d later, and
CD4+ T cells were purified and stimulated
in vitro with LCMV-infected splenic APCs.
(B) Proliferation was assessed 3 d later by
[3H]thymidine incorporation. Results are
shown as mean ± SEM for three mice per
group. (C) Secretion of IFN- was assessed
from culture supernatants by ELISA. Results
are shown as mean ± SEM from three mice
per group. Identical results were obtained
with the LCMV-derived class II binding
peptide 13 (data not shown). One representative experiment of two is shown.
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LCMV-specific CD4+ T cell responses were then examined early after infection (day 13) in TR-Fc-treated control
and CD40-deficient mice by measuring in vitro recall proliferative responses. As reported previously (19), LCMV-specific CD4+ T cells produced a Th1 cytokine pattern, since large
amounts of IFN- (Fig. 3 C) but not IL-4 (data not shown)
were detected in culture supernatants. Purified CD4+ T cells
from CD40-deficient mice proliferated normally and produced, although at reduced levels, IFN- after stimulation
with LCMV-derived antigens (Fig. 3, B and C), indicating
that LCMV can prime antigen-specific CD4+ T cells in a
CD40L/CD40-independent manner. TR-Fc-treated control mice also mounted normal CD4+ T cell responses (Fig.
3, B and C). In marked contrast, the proliferative response
of CD4+ T cells in TR-Fc-treated CD40-deficient mice
was nearly completely blocked (Fig. 3 B). In addition, the
production of IFN- was also completely abrogated in
these mice (Fig. 3 C). This was not due to immune deviation, since blocking the TRANCE/TRANCE-R interaction in control or CD40-deficient mice did not upregulate
IL-4 production (data not shown). To determine whether
the lack of LCMV-specific CD4+ T cell responses was due
to a delay in T cell priming in the absence of both CD40L/
CD40 and TRANCE/TRANCE-R interactions, CD4+
T cells were purified and restimulated with viral antigens
1 mo after infection. Even 30 d after infection, no significant LCMV-specific CD4+ T cell responses were detected
in the absence of both CD40L/CD40 and TRANCE/
TRANCE-R interactions (Fig. 4). Therefore, the results indicate that either the CD40L/CD40 or the TRANCE/
TRANCE-R interaction is required for induction of CD4+
T cell responses by LCMV.
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Fig. 4.
LCMV-specific CD4+ T cell
responses at a later time point. C57BL/6
mice (triangles) or CD40-deficient mice
(circles) were infected with LCMV and
treated with either TR-Fc (filled symbols)
or control hIgG1 (open symbols). Spleen
cells were isolated 30 d later, and CD4+ T
cells were purified and stimulated in vitro
with LCMV-infected splenic APCs. (A)
Proliferation was assessed 3 d later by
[3H]thymidine incorporation. Results are
shown as mean ± SEM of triplicate values
from pooled spleen cells of three mice per
group. (B) Secretion of IFN- was assessed
from culture supernatants by ELISA. Results
are shown as mean ± SEM of triplicate values from pooled spleen cells of three mice
per group. Identical results were obtained
with the LCMV-derived class II binding
peptide 13 (data not shown). One representative experiment of two is shown.
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To analyze whether TRANCE can also mediate CD40L/
CD40-independent CD4+ T cell responses in other viral systems, CD40-deficient mice were infected with influenza virus,
and virus-specific CD4+ T cell responses were analyzed (Fig.
5). As observed for LCMV, influenza virus can prime antigen-specific CD4+ T cells in a CD40L/CD40-independent manner, and the induction of virus-specific CD4+ T cell responses
was greatly inhibited in the TR-Fc-treated CD40-deficient mice (Fig. 5). Thus, TRANCE/TRANCE-R provides a major costimulatory stimulus in the absence of CD40L/CD40 for
CD4+ T cell responses to influenza viruses.
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Fig. 5.
TRANCE plays a role in influenza virus-specific CD4+ T
cell responses. CD40-deficient mice were infected with influenza virus
and treated with either TR-Fc (filled circles) or control hIgG1 (open circles). Spleen cells were isolated 8 d later, and CD4+ T cells were purified
and restimulated in vitro with UV light-inactivated influenza viruses. (A)
Proliferation was assessed 3 d later by [3H]thymidine incorporation. Results are shown as mean ± SEM from triplicate values from pooled spleen
cells of three mice per group. Background proliferation is subtracted. (B)
Secretion of IFN- was assessed from culture supernatants by ELISA. Results are shown as mean ± SEM from three mice per group. Background
is <2 U/ml. One representative experiment of three is shown.
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In summary, this study establishes the TRANCE/
TRANCE-R interaction as an important player in CD4+
T cell responses in vivo. Moreover, we also show that the
TRANCE/TRANCE-R interaction compensates for a
lack of CD40L/CD40 interaction to allow efficient CD4+
T cell responses during viral infection. This explains why
viruses can induce CD4+ T cell immune responses in
CD40L- or CD40-deficient mice. In addition, this study
also shows that despite the destruction of infected cells and
the production of various inflammatory cytokines in response
to viral infection, efficient CD4+ T cell priming still requires
costimulation predominantly by TNF family members (i.e.,
either TRANCE or CD40L), which is analogous to CD4+
T cell priming induced by purified proteins administered
with CFA (in this case, costimulation provided by CD40L).
Therefore, it is possible that CD4+ T cell priming in general may require costimulation by at least one TNF family
member (e.g., CD40L or TRANCE).
CD40L-mediated CD4+ T cell activation occurs indirectly via activation of the APCs (1, 9). Specifically,
in vitro stimulation of CD40 on DCs stimulates a maturation process culminating in the upregulation of costimulatory molecules and the capacity to produce IL-12, a cytokine important for production of IFN- by CD4+ T cells
(1, 9). Although stimulation of TRANCE-R on mature DCs fails to upregulate costimulatory molecules on these
cells (24), we showed that, similar to CD40L, TRANCE
treatment triggered generation of IL-12 and other proinflammatory cytokines by mature DCs. In addition, when
stimulated in vitro by anti-CD3, purified T cells proliferated and produced normal levels of cytokines in the presence of TR-Fc (data not shown), suggesting that, similar to
the CD40L/CD40 interaction, there is no direct role for the TRANCE/TRANCE-R interaction in T cells. Therefore,
the TRANCE/TRANCE-R and CD40L/CD40 interactions between CD4+ T cells and APCs may have functional
consequences primarily for the APCs, e.g., promoting DC
viability and cytokine production (1, 9, 24). It is presently not known why some antigens (e.g., proteins in adjuvants) use predominantly the CD40L-dependent pathway (1) while others (e.g., viruses [this study]) use both TRANCE- and CD40L-dependent pathways of CD4+
T cell stimulation. It is possible that certain viruses directly upregulate TRANCE-R during DC differentiation. Alternatively, there may be different requirements for induction
of TRANCE and CD40L on T cells. It is also possible, although not yet determined, that some pathogens might use
predominantly the TRANCE-dependent pathway to elicit
efficient CD4+ T cell responses. The CD40L/CD40 interaction is an important site for manipulating the immune response in order to facilitate organ transplantation and to reduce atherosclerosis (1, 29), and our in vivo findings now
suggest that the interaction of TRANCE and its receptor
may be an additional target for immunotherapy.
| |
Footnotes |
Address correspondence to Martin F. Bachmann, Basel Institute for Immunology, Grenzacherstrasse 487, CH 4005 Basel, Switzerland. Phone: 41-61-605-1228; Fax: 41-61-605-1364; E-mail: bachmann{at}bii.ch; or
to Yongwon Choi, Laboratory of Immunology, The Rockefeller University, 1230 York Ave., New York,
NY 10021. Phone: 212-327-7441; Fax: 212-327-7319; E-mail: choi{at}rockvax.rockefeller.edu
Received for publication 8 January 1999.
The Basel Institute for Immunology was founded and is supported by F. Hoffmann-La Roche, Basel, Switzerland. This work was supported in part by National Institutes of Health Medical Scientist Training Program grant GM-07739 (to B.R. Wong), and National Institutes of Health grants AI-44264 (to Y. Choi),
AI-13013 (to R.M. Steinman), and AI-39672 (to R.M. Steinman). R. Josien is supported by a fellowship from the Revson Foundation. Y. Choi is an investigator of the Howard Hughes Medical Institute.
We thank Manfred Kopf and Marco Colonna for comments and critical discussion. We also thank Angela
Santana, Hong-Li Li, and Barbara Ecabert for excellent technical assistance.
Abbreviations used in this paper
DC, dendritic cell;
GC, germinal center;
LCMV, lymphocytic choriomeningitis virus;
TRANCE, TNF-related
activation-induced cytokine.
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