Perspective

The B7/CD28/CTLA4 T-Cell Activation Pathway

Implications for Inflammatory Lung Disease
Jonathan M. Green
Departments of Medicine and Pathology, Washington University School of Medicine, St. Louis, Missouri

The molecular events that modulate the T-cell response to

antigen are key determinants in the outcome of pulmonary immune responses. Over the past several years, it has
become evident that the B7:CD28 costimulation pathway
is a critical regulator of T-cell responses both in vitro and
in vivo. Given its importance in T-cell activation and its
potential as a target for immune-based therapies, this perspective will review the current data on the regulation of
T-cell activation by the B7 costimulatory pathway.
In 1970 Bretscher and Cohn put forth the two-signal
model of lymphocyte activation to explain self/nonself discrimination (1). This model proposes that T-cell activation
requires two independent signals. The first is transduced
through the T-cell receptor (TCR) after engagement by
antigen; and the second, costimulatory signal is delivered
by ligation of a distinct receptor present on the surface of
the T cell. This model predicts that engagement of the
TCR in the absence of costimulation will fail to activate
the T cell. A substantial body of evidence has accumulated
in support of this hypothesis. Early studies demonstrated
that antigen presented by chemically fixed antigen-presenting cells (APCs) resulted in a failure of T-cell activation and rendered them unresponsive to further antigenic
stimulation, a process termed induction of anergy. This
was shown to be the result of the inability of the fixed
APCs to engage costimulatory molecules, in particular
CD28 (2). The anergic T cell fails to produce the autocrine
growth factor interleukin-2 (IL-2) upon stimulation, and
addition of exogenous IL-2 can reverse the anergic state (3).
The molecular basis for costimulation remained elusive
until the cloning of CD28 by Arrufo and Seed in 1987 (4).
First termed Tp44, crosslinking of CD28 was initially
shown to augment the proliferative response of T cells in
1984 (5). CD28 enables T cells to proliferate in the presence of the immunosuppressant cyclosporine A (6). Cytokine expression is markedly enhanced after CD28 costimulation through both transcriptional activation and
(Received in original form January 3, 2000)
Address correspondence to: Jonathan M. Green, M.D., Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, 660 S. Euclid Ave, Box 8052, St. Louis, MO 63110. Email: jgreen@
pulmonary.wustl.edu
Abbreviations: antigen-presenting cells, APC; cytotoxic T-lymphocyte antigen, CTLA; interleukin 2, IL-2; messenger RNA, mRNA; T helper, Th.
Am. J. Respir. Cell Mol. Biol. Vol. 22, pp. 261264, 2000
Internet address: www.atsjournals.org

posttranscriptional stabilization of messenger RNA (mRNA)

(7). In addition to these effects, CD28 also regulates cell
survival by induction of the anti-apoptotic protein Bcl-XL
and activation of the protein kinase Akt (8).
CD28 has two ligands, B7-1 (CD80) and B7-2 (CD86).
B7-1 was identified as an adhesion receptor on B cells that
interacted specifically with CD28 (9, 10). Subsequent work
led to the identification of a second member of the B7 family,
B7-2, which also bound CD28 (1113). The greater complexity of the system became evident with the identification of an additional counter-receptor on T cells, cytotoxic
T-lymphocyte antigen 4 (CTLA4), which could bind both
B7-1 and B7-2 (14, 15). In contrast to CD28, CTLA4 is expressed only on activated T cells and is a negative regulator of T-cell function (16). CTLA4-deficient mice manifest
massive lymphoproliferative disease, which is lethal by 3 wk
of age (17, 18).
Recently, new members of the B7/CD28 family have
been identified. The search for new tumor necrosis factor
(TNF)inducible, nuclear factor B (NFB)dependent
genes led to the cloning of B7h (19). This protein shares
sequence homology with both B7-1 and B7-2 but does not
bind to either CD28 or CTLA4. Instead, it binds to a newly
identified CD28 homolog, inducible costimulator (ICOS),
which is expressed on a subset of activated T cells (20). In
addition, Dong and colleagues report the cloning of another B7 homolog, B7-H1, which may be the human ortholog
of B7h (21). The role of these new B7/CD28 family members in the immune response remains to be explored.
The importance of CD28 in in vivo immune responses
was highlighted by early studies examining transplant rejection. Blockade of B7 with CTLA4Ig, a soluble inhibitor of
B7-1 and B7-2, led to prolonged graft survival after both
heterotopic cardiac transplantation in rats and islet-cell xenografts in mice (22, 23). Intriguing results have also been
found in the manipulation of B7:CD28:CTLA4 interactions
in tumor immunity. Transfection of B7 into murine melanoma cells led to effective antitumor responses in vivo (24).
Prevention of negative signaling through CTLA4 resulted
in regression of primary tumors, as well as augmented secondary responses upon tumor rechallenge in mice (25).
In addition to its role in the initial activation of naive T
cells, recent work has examined whether CD28 influences
the subsequent differentiation of CD4 T cells. Blockade
of B7-1 in experimental autoimmune encephelomyelitis
led to a reduction in disease severity and promotion of T
helper (Th)2-cell development (26). In contrast, blockade

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AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY VOL. 22 2000

Figure 1. T-cell activation

is modulated by B7CD28
CTLA4 interactions. The B7
family members B7-1 and
B7-2 both interact with CD28
and CTLA4 to either positively or negatively regulate
the T-cell response to antigen. The balance of these signals determine whether TCR
engagement results in T-cell
activation and development
of effector function, or unresponsiveness and programmed
cell death.

of B7-2 resulted in an increase in disease severity. CD28mediated events were protective in the development of
hyperglycemia in nonobese diabetic mice, perhaps by promoting the development of Th2 cells (27). Similarly, in
models of parasitic disease, CD28 has been shown to promote Th2-cell development (28). However, some conflicting results have been noted in the comparison of models
that use CTLA4Ig with mice deficient in CD28 expression.
For example, Corry and associates found that a single injection of CTLA4Ig could render normally susceptible
BALB/c mice resistant to Leishmania major infection
(29). However, examination of CD28-deficient mice in the
C57Bl/6 and BALB/c background demonstrated normal
Th1 and Th2 responses to L. major infection (30). Thus,
the precise role that CD28 plays in Th-cell differentiation
remains to be defined.
In this issue of the Red Journal, Mark and coworkers
examine the development of airway inflammation in B7deficient mice (31). They demonstrate that B7-1 and B7-2
have overlapping and complementary roles in directing the
T-cell response to inhaled antigen challenge. Blockade of
B7 was first shown in 1996 to completely abrogate airway
inflammation and hyperresponsiveness in a murine model
of allergic airway inflammation (32). Importantly, treatment with the inhibitor was effective even if the mice had
been previously sensitized to the antigen in the absence of
CTLA4Ig. Thus, the B7 blockade exerted effects on the effector phase of the response. These results have been subsequently confirmed by several other investigators (3335).
Similar to the results found in the use of B7 inhibitors in
wild-type mice, CD28-deficient mice do not exhibit airway
inflammation after inhaled antigen challenge ([35]; J. S.
Burr and J. M. Green, unpublished results).
CTLA4 also exerts an important regulatory influence
on in vivo immune responses. CTLA4 is engaged by both
B7-1 and B7-2, but in contrast to CD28, CTLA4 ligation
results in a decrease in proliferation and IL-2 production
(36). Thus, the failure of CD28-deficient mice to respond
to stimulation might be due to unopposed negative signal-

ing through CTLA4. In vitro studies in the CD28-deficient

mice were unable to detect such an effect; however, recent
in vivo studies of cardiac transplantation suggest otherwise
(37). B7 blockade in CD28-deficient mice that had received a heterotopic, allogeneic cardiac transplant resulted
in accelerated graft rejection (38). These data suggest that
the prolonged graft survival in untreated CD28-deficient
mice may be the result of the inhibition of T-cell function
by CTLA4.
Despite the impressive array of biologic effects mediated by CD28 and CTLA4, the precise mechanism by
which these receptors function remains unclear. The topologic model of T-cell activation proposes that costimulatory molecules serve primarily to stabilize the formation of
the T cell/APC contact, a structure termed the immunologic synapse (39). Alternatively, these receptors may independently initiate signal transduction pathways that are
integrated with TCR-derived signals either at the level of
gene transcription or at a prenuclear level.
Several observations argue against a purely topologic
model. First, CD28 ligation is effective even when not
colocalized with the TCR (40). Second, CD28 imparts
properties to the T cell that cannot be mimicked by TCR
engagement alone, such as cyclosporin resistance, enhanced cell survival, and stabilization of cytokine mRNA
by induction of specific RNA-binding proteins (41).
Work by two independent groups have proposed alternative mechanisms for CD28-mediated costimulation. Ligation of CD28 promotes reorganization of the actin cytoskeleton and the directed transport of T-cell surface
receptors to the TCR contact cap (42). Similarly, ligation
of CD28 causes the formation of specialized membrane
microdomains termed rafts (43). These structures are complexes of proteins in cholesterol-rich regions of the plasma
membrane that assemble key signaling components. In
this manner, CD28 might facilitate TCR signaling while
initiating novel signal transduction pathways.
Two regions of the cytoplasmic tail of CD28 have been
identified as important in mediating function. The first is a
YMNM motif that can directly bind and activate phosphatidyl inositol 3-kinase (PI3K). However, the absolute
requirement for this has been controversial, with some
studies demonstrating an absolute dependence on this motif, whereas others show no such requirement (44, 45). In
addition, this same region may mediate binding to the
adapter protein Grb-2 and may also mediate activation of
the Tec family kinase Itk (46). Studies have also identified
a C terminal, proline-rich region as required for regulation
of proliferation and IL-2 secretion by CD28. Deletion of
this region was found to abrogate the regulation of IL-2
gene transcription in Jurkat cells (47). Recently, we have
demonstrated that specific proline residues at positions
187 and 190 are absolutely required for costimulation on
primary T cells by retroviral reconstitution of primary T
lymphocytes from CD28-deficient mice (48). These residues appear to mediate the binding and direct activation
of the Src family kinase Lck. Activation of Lck could function to amplify TCR-derived signals and integrate CD28 at
the level of phosphorylation of the zeta chain of CD3, as
well as lead to direct activation of the Ras/mitogen-activated protein kinase pathway.

Perspective

The mechanism by which CTLA4 modulates T-cell responsiveness also remains unclear. The cytoplasmic tail of
CTLA4 contains a tyrosine-based motif that can bind
PI3K (49). In addition, CTLA4 can bind to the protein tyrosine phosphatase SHP-2 (50, 51). Recruitment of SHP-2
to the TCR/CD3 complex could result in the dephosphorylation of components of the signaling complex and could
terminate TCR-mediated cellular activation. However,
transfection of a mutant CTLA4 construct, lacking all but
seven amino acids of the cytoplasmic tail, retained the
ability to suppress IL-2 production in T-cell clones, raising
the possibility of additional mechanisms by which CTLA4
functions (52). Alternatively, CTLA4 may inhibit T-cell
activation by restricting the availability of B7 to interact
with CD28. CTLA4 has approximately a 20-fold higher affinity for B7 than CD28, and the unchecked proliferation
of CTLA4-deficient T cells is dependent upon CD28 engagement of B7 (53).
Although the precise biochemical mechanism through
which both CD28 and CTLA4 function remains controversial, their importance in the regulation of immune responses is clear. Interaction of the TCR with the Ag/major
histocompatibility complex remains the critical initiating
event in T-cell activation; however, the balance of
CD28:CTLA4derived signals profoundly alter the outcome of that event. Thus, both of these pathways have tremendous potential for therapeutic manipulation in a wide
range of conditions, from transplant rejection to autoimmunity to asthma.
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