By
From the * Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of
Medicine, New Haven, Connecticut 06510
Almost a decade ago, major advancements in our understanding of the cell-cell interactions that were critically involved in the regulation of the immune response
were achieved when it was established that T cell activation
not only required a signal through the T cell receptor but
also a second signal generated by the interaction of costimulatory molecules CD80 and CD86 on the surface of APCs
and CD28 or CTLA-4 on T cells (1). Since then, identification of other molecular interactions that are important in
regulating the immune response has increased dramatically, elucidating signals that enhance stable cellular interactions between APCs and T cells as well as apoptotic signals that
regulate survival of either the APC or the T cell (2, 3). One
molecular interaction that has received enormous attention
is that between CD40 on APCs and CD154 on T cells (reviewed in 4). CD40-CD154 signals are a vital component
in the generation of humoral immunity, as exemplified by
murine models in which blockade of CD40-CD154 signals, either by antibodies or the creation of a null mutation in CD154, abrogates development of B cell responses to
thymus-dependent antigens (5, 6). Signals through CD40
can also influence the activity of other APCs, in particular
dendritic cells (DCs), leading to the upregulation of adhesion and costimulatory molecules (7, 8), increased accumulation of peptide-MHC complexes on DC surfaces, and the
generation of antiapoptotic signals that increase DC survival (9, 10), thus helping to prolong contact between DCs
and T cells. Although the importance of CD40-CD154 interactions in the generation of B and T cell immunity are
indisputable, findings that CD40- and CD154-deficient mice
can mount T cell responses to certain viral infections have
suggested a novel CD40-CD154-independent pathway involved in the activation of T cells (11). In this issue,
Bachmann et al. (14) provide compelling evidence that this
CD40-CD154-independent pathway for T cell activation
involves interaction between a newly described molecule,
TRANCE (TNF-related activation-induced cytokine), on
T cells and its cognate receptor, RANK (receptor activator
of NF TRANCE (also called receptor activator of NF In this issue, Bachmann et al. expand on these earlier
findings, demonstrating that TRANCE not only shares sequence homology to CD154 but shares several of its functional properties as well. For example, treatment of mature
DCs with TRANCE increases expression of inflammatory
cytokines, such as IL-1 and IL-6, and secretion of IL-12,
which can promote differentiation of CD4+ T cells into
Th1 cells (17). Furthermore, TRANCE treatment of DCs
prolongs the life span of DCs by upregulating BclXL expression, another property shared with CD154 (18). These striking functional similarities between TRANCE and CD154
led Bachmann et al. to determine whether signaling through
the TRANCE-RANK pathway could substitute for CD154-
CD40 signals in the generation of immunity to viral infections. To address this, they used the well defined lymphocytic choriomeningitis virus (LCMV) infection as a murine
model, as CD4+ T cell responses to LCMV infections have
been shown to be independent of CD154 (11). Preliminary
analysis demonstrated that LCMV infection upregulated
TRANCE on both CD4+ and CD8+ T cells, yet TRANCE-
RANK signals were not vital for the generation of humoral
or cell-mediated immunity to LCMV in mice that could utilize the CD40-CD154 signaling pathway, as blockade of
TRANCE signaling by injection of soluble TRANCE-R-
human IgG1 Fc fusion protein (Tr-Fc) had little impact in
abrogating either type of immunity to LCMV. The same
could not be said when the experiments were repeated
in CD40-deficient mice. In these animals, inhibition of
TRANCE signaling led to an almost complete block in the
generation of CD4+ T cell immunity to LCMV and total
abrogation of IFN- Much of our understanding of the importance of
TRANCE-RANK signals has centered on analyzing the
impact such signals have on the efficacy of DCs in activating T cells, and this is due in part to the evidence that
RANK expression seems to be restricted to DCs. However, there is now evidence to suggest that TRANCE is
also critically involved in the development of B and T cells as well as lymph node organogenesis. This is based on the
interesting studies by Kong et al. (19), who recently described the phenotype of mice carrying a null mutation for
osteoprotegerin ligand (TRANCE/opgl The necessity for TRANCE signals in the development of
the immune system was not restricted to the thymic compartment. Indeed, a similar role for TRANCE in the progression of B cells from the B220+CD43+ and B220+CD25 In light of this evidence that TRANCE is involved in
the development of T and B cells, it can be imagined that
TRANCE would also be important in the development of
other bone marrow-derived cells such as DCs and monocytes. In support of this idea, it has been recently shown
that monocyte cell lines can differentiate into osteoclasts if
cultured with colony stimulating factor-1 and TRANCE
(20, 21), suggesting that macrophages, DCs, and osteoclasts
may share a common committed precursor. Furthermore, as stated above, TRANCE can act as a survival signal for
DCs by enhancing expression of apoptosis inhibitor BclXL
(15). However, FACS® analysis of splenic DC populations
in TRANCE/opgl One last, intriguing finding relating to the development
of the immune system found in TRANCE/opgl In conclusion, the findings by Bachmann et al. and Kong et
al. have highlighted two novel points at which TRANCE-
RANK signals have a critical role to play in the immune
system. The first occurs at the earliest stages of B and T
cell development in the bone marrow and thymus, respectively, where TRANCE signals are necessary for progression to the pre-B and pre-T cell stages. The second occurs
in the mature immune system and is restricted to interactions between DCs and T cells. This latter role for
TRANCE is intriguing. Regulating the interaction between CD40 and CD154 is one of the most vital routes to
controlling immune responses and preventing the inadvertent activation of autoreactive T cells. However, certain viral infections or simple inflammatory responses can utilize a
CD40-CD154-independent pathway (12, 13, 29) and lead
to the generation of autoaggressive responses to self tissue.
If these viruses are using the TRANCE-RANK route for
activation of autoreactive T cells, then the findings presented by Bachmann et al. may provide insight into the design of novel therapeutic strategies that can circumvent
CD40-CD154-independent activation of autoreactive T cells,
thereby protecting against deleterious immune responses.
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B), on DCs.
B ligand
[RANKL], osteoprotegerin ligand [TRANCE/OPGL],
and osteoclast differentiation factor [ODF]) was discovered
almost simultaneously by two groups during attempts to
clone novel genes involved in the regulation of apoptosis
and function of DCs (15, 16). TRANCE is a member of
the TNF ligand superfamily that includes Fas ligand, CD27, CD30, CD154, 4-1BBL, OX40L, TNF-
, lymphotoxin
(LT)
/
, and TRAIL (TNF-related apoptosis-inducing
ligand). Sequence analysis has shown that the extracellular
domain of TRANCE shares 18-28% amino acid identity
with other members of the TNF superfamily and the greatest
identity with CD154 (16). Furthermore, TRANCE has been mapped to chromosome location 13q14 in humans,
where the first TNF ligand family member genes have
also been located. Extensive studies relating to the pattern
of expression of TRANCE mRNA demonstrated that the
highest levels of mRNA were detectable in lymph nodes and
restricted to T cells. The ligand for TRANCE is RANK, a
member of the TNFR superfamily that shares, like TRANCE
with the TNF superfamily, remarkable sequence homology
with other members of the TNFR superfamily, CD40 in
particular; its chromosomal location has been mapped to
position 18q22.1 in humans, where TNFR family members reside. Although RANK mRNA can be detected in
skeletal muscle, thymus, liver, colon, small intestine, and adrenal gland, at the protein level, RANK expression is only
detectable on the surfaces of mature DCs, suggesting that
RANK expression is posttranscriptionally regulated. At the
cell surface level, RANK expression is dependent on the activation of T cells, as surface expression of RANK is rarely
detectable in the absence of cytokines (16).
production, which is normally inducible following LCMV infection of CD40-deficient mice
(11). These data suggest that TRANCE-RANK signals do
not override CD40-CD154 signals in the regulation of the
immune response; rather, TRANCE-RANK signaling offers an alternative route for the activation of T cells.
/
mice). Originally generated to address the role of TRANCE/OPGL in
osteoclast differentiation, they found that, in addition to the expected osteopetrosis and defects in tooth formation,
TRANCE/opgl
/
mice had defects in their lymphoid
compartments (19). The first evidence that TRANCE/OPGL
is involved in the development of the immune system
was based on the observation that thymi from TRANCE/ opgl
/
mice were significantly decreased in size. This abnormality was found to be due to a selective block in the
transition from the CD44
CD25+ stage of thymocyte development to the CD44
CD25+ stage, when the TCR is
first expressed. Blockade in T cell development was not absolute, and thymocytes that could bypass the blockade developed into the normal ratio of CD4+ and CD8+ single
positive cells. The thymic abnormality in TRANCE/opgl
/
mice was found to be intrinsic to bone marrow-derived
cells, as T cell development was normal in TRANCE/
opgl+/
rag1
/
and TRANCE/opgl+/+rag1
/
chimeric
mice, whereas TRANCE/opgl
/
rag1
/
chimeric mice
showed pronounced blockade in the transition from the
CD44
CD25+ to CD44
CD25+ stage.
pro-B cell stage to the B220+CD43
, B220+CD25+, and
B220+sIgM+ pre-B cell precursors in the bone marrow
was seen in TRANCE/opgl
/
mice.
/
mice suggested that TRANCE was
not involved in DC development, as normal numbers of
CD11c+ DCs were detected in the spleens of TRANCE/
opgl
/
and TRANCE/opgl+/
littermates. Also, there was
no suggestion that TRANCE was required for the expression of costimulatory molecules, adhesion molecules, or
CD40, as similar levels of these molecules were expressed
on DCs from TRANCE/opgl
/
, TRANCE/opgl+/
,
and TRANCE/opgl+/+ mice. In addition, functional analysis of DCs from TRANCE/opgl
/
mice revealed that
they had the same capacity as DCs from TRANCE/opgl+/+
mice to stimulate allogeneic T cells from normal BALB/c
mice at the level of both proliferation and cytokine production. The apparent noninvolvement of TRANCE in
DC development was not restricted to the DCs located in
the spleen, as there were also no distinct differences in the
development of DCs present in the skin and thymi of
TRANCE/opgl
/
and TRANCE/opgl+/+ mice. Despite
this inability to detect abnormalities in the DC compartment of TRANCE/opgl
/
mice, T cells that have managed to overcome the thymic block are defective in their
capacity to mount allogeneic responses. Thus, T cells from
TRANCE/opgl
/
mice stimulated with allogeneic
BALB/c splenic DCs showed reduced production of IL-2
and IFN-
compared with T cells from TRANCE/opgl+/+
mice. The defect in T cell responses was also apparent following stimulation with anti-CD3 and anti-CD28 cross-linking antibodies and occurred in both the Th1 and Th2
compartments. It would seem, therefore, that although
TRANCE-RANK signals are not important for the generation of a fully functional DC, the RANK-TRANCE signal from the DC to the T cell is a critical requirement for
the optimum activation of T cells.
/
mice
was that such mice lacked lymph nodes yet showed normal Peyer's patches and splenic architecture. Lymph nodes are
critical components in the generation of B and T cell immunity, as it is within these unique lymphoid structures
that naive T cells first encounter their cognate antigens.
The molecular interactions involved in the formation and
organization of lymph node architecture have been documented and involve signaling through TNF and TNFR
family members, including LT
, LT
, TNF-
, and CD40.
For example, mice deficient in LT
lack Peyer's patches
and peripheral lymph nodes, but, in general, still possess
mesenteric lymph nodes (22); in LT
-deficient mice, however, all lymph nodes are absent (23). In both of these
cited cases and in the case of animals deficient in TNFR1 or
TNF, there are also aberrations in splenic architecture (27,
28), a finding that is not seen in TRANCE/opgl
/
mice.
Thus, it would seem that TRANCE is specifically involved in the generation of lymph nodes, with no apparent role to
play in the formation of Peyer's patches or the spleen. The
reason for the lack of lymph node development in
TRANCE/opgl
/
mice is still unknown, though it does
not seem to relate to defects in the homing of B and T cells
nor to problems associated with abnormalities in bone marrow-derived cells.
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Footnotes |
---|
Address correspondence to Richard A. Flavell, Section of Immunobiology, Howard Hughes Medical Institute, 310 Cedar St., FMB412, Yale University School of Medicine, New Haven, CT 06520-8011. Phone: 203-785-7024; Fax: 203-785-7561; E-mail: fran.manzo{at}qm.yale.edu
Received for publication 23 February 1999.
E.A. Green is the recipient of a Juvenile Diabetes Foundation International Fellowship (No. 397021). R.A. Flavell is an Investigator of the Howard Hughes Medical Institute.We thank Fran Manzo for secretarial help in preparing this manuscript.
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