14
THE ROLE OF T-CELLS IN
CHRONIC B-LYMPHOCYTIC LEUKEMIA
AD DONNENBERG AND VS DONNENBERG
ABSTRACT
Chronic B-cell lymphocytic leukemia (B-CLL) has
a unique natural history characterized by a long period during which a
clonal B-cell lymphocytosis may be the only sign. The events involved in
the maintenance of this state and the evolution of the disease process
are poorly understood. In addition to the increased number of small resting
B-cells, which characterizes early stages of disease, a small population
of large atypical lymphocytes is a frequent finding. We have determined
that these cells include a population of activated T-lymphocytes which
account for 10-60% of the large lymphocytes. In this review, we postulate
an autoimmune-like short circuit in the interactions between T-cells and
the nascent B-CLL clone, which confers a great selective advantage on the
clone. According to this interpretation, its continuous expansion culminates,
over time, in frank disease manifestations. The hypothesis that helper
T-cells play a key role in the evolution of B-CLL suggests a series of
experiments exploring T-cell/B-CLL interactions, and if correct identifies
a new target for therapeutic intervention.
INTRODUCTION
Natural History of B-CLL
Chronic B-cell lymphocytic leukemia is the most
common leukemia in the United States with an annual incidence estimated
at 3 cases per 100,000 persons (1). In persons over age 60 the annual incidence
exceeds 20 cases per 100,000 (2). Although B-CLL has traditionally been
characterized as a disease of the elderly, the ability to detect clonal
B-cell expansion by flow cytometry has provided data which are causing
us to revise our view of its natural history. CLL often begins insidiously
in mid-life; in the initial stages clonal B-cell lymphocytosis may be the
only finding. Because of this clinically inapparent onset, diagnosis is
often incidental and the early natural history has been difficult to study.
Despite (or perhaps because of) its indolent course, B-CLL is presently
considered incurable (3). As the lymphocytosis progresses over the course
of years, anemia, thrombocytopenia and increased susceptibility to infection
become significant disease manifestations. Less commonly, B-CLL is marked
by a progression to prolymphocytic leukemia or other B-cell malignancies.
Prolymphocytic leukemias almost always arise from the B-CLL clone, whereas
about half of the large B-cell lymphomas, acute lymphoblastic leukemias
and multiple myelomas developing after B-CLL are genetically unrelated
(4). Autoimmune disorders and unrelated neoplasms may also complicate the
course of advanced B-CLL. Although B-CLL is a clonal proliferative disorder,
chromosomal abnormalities are varied, can only be demonstrated in about
half of B-CLL cases, and are less frequent in early disease (5). Prognosis
is still best assessed by a relatively simple clinical staging procedure,
although chromosomal abnormalities, bone marrow histology, immunophenotype
and lymphocyte count doubling time have also been reported as predictors
of disease progression. The Rai classification (6) recognizes 5 stages
(0-IV) based on hemogram and physical examination (Table 1). This has been
condensed into 3 categories which differ with respect to survival: good
prognosis (Rai Stage 0), intermediate prognosis (stages I and II) and poor
prognosis (stages III and IV). The routine use of flow cytometry to investigate
the cause of persistent elevated lymphocyte counts has resulted in the
occasional detection of clonal B-cell populations (by clonal excess of
kappa or lambda light chains) in the absence of marrow lymphocytosis, suggesting
a category preceding Rai stage 0.
B-CLL displays functional and phenotypic characteristics
of mantle zone B-cells
Many similarities between B-CLL cells and normal
mantle zone B-cells have been documented (7, 8). The small clonal B-lymphocytes
of B-CLL usually express low levels of membrane immunoglobulin (IgM, IgD
or both) and CD5, a glycoprotein present on follicular B-cells, a subset
of peripheral B-cells, and almost all normal T-lymphocytes (see below).
In addition, most B-CLL cells express HLA-DR, CD19, CD20, CD21, CD24, and
CD37, which are also present on normal mature B-cells. Most B-CLL also
express CD23 which has received attention as a potential B-cell autocrine
growth factor (9). Most do not express CD10 (common acute lymphocytic leukemia
antigen) or other early markers found in other B-cell neoplasms. Additional
markers commonly expressed on B-CLL include CD27, CD39 and NuB1. KiB3,
7F7, and CD25 may be absent or present. Taken together, these populations
bear a marked resemblance to cellular subsets in the mantle zone (10).
In addition, expression of bcl-2 is high in B-CLL cells and in normal tonsillar
follicular mantle zone B-cells, but not in germinal center B-cells or normal
peripheral CD5+ B-cells (11). Thus, for the majority of early B-CLL cases,
which do not express chromosomal abnormalities or markers discordant with
respect to lineage or differentiation, their “normal” phenotype contrasts
strikingly with the remarkable tumor mass regularly attained by the B-CLL
clone. As an example, consider a Rai stage 0 patient (without demonstrable
lymph node, spleen or liver involvement) in whom a typical B-cell count
of 50,000/mL multiplied by the blood volume (5L) yields a total of 2.5x10
11 clonal B-cells. This estimate is conservative since it fails to take
into account tumor in the bone marrow, lymph nodes and spleen.
REGULATION OF B-CELL GROWTH AND
DIFFERENTIATION
T-B lymphocyte interactions regulate the proliferation
of mature B-lymphocytes and the synthesis of antibody directed against
T-dependent antigens. It is now recognized that this process involves
a lively multiway conversation between CD4+ helper T cells (T h ), B-cells
and a variety of professional and part time antigen presenting cells (APC)
(reviewed in 12). The molecular mediators of such cellular conversations
include an array of signaling molecules, adhesion molecules, growth factors
and their receptors. Because B-CLL growth and differentiation appear to
stop short at a stage equivalent to that of the resting mantle zone B-cell,
it is useful to review the events leading to this stage. Recent studies
have focused on two ligand-receptor interactions which appear to be proximate
to the initiation of APC/T-cell and T-cell/B-cell interactions, respectively
(reviewed in 13). Th cells recognize processed antigen presented in the
context of MHC class II (HLA DR) via the T cell antigen receptor (TCR).
Although there are a variety of costimuli which can augment this process,
the critical event which prevents Th anergy and favors activation and cytokine
release appears to be the interaction of B7.1/B7.2 (induced or upregulated
on the APC) with CD28 (constitutively expressed on the Th cell).
B-cells themselves can serve as APC, and in murine systems, favor the generation
of Th-2 over Th-1 (38). Once activated through their TCR, T-cells transiently
express CD40 ligand (CD40L) which upon contact with CD40 (constitutively
expressed on B-cells) induces the expression of growth factor receptor
(IL-4R) and CD80 (B7.1) in resting B-cells.
Th-1 versus Th-2 in freshly isolated human cell
Helper T-cells have been classified as Th-0, Th-1
or Th-2 on the basis of cytokine production patterns. Th-1 is equated with
the production of IL-2 and IFN-g (limited B-cell help, DTH, macrophage
activation, cytotoxicity) whereas Th-2 produce IL-4, IL-5, IL-9 and IL-10
(B-cell help). Th-0 cells, which in some schemes are thought to represent
a common precursor of Th-1 and Th-2, produce IL-2, IL-4, IL-5, GM-CSF and
IFN-g. In mouse and in man, characterization of Th-subsets has been accomplished
by the analysis of long term T-cell lines and clones. In short term bulk
activated cells, these characteristic cytokine patterns are easily obscured
by the heterogeneity of responsive cells and the presence of cells of transitional
phenotypes. Recently a population of short term, bulk activated T-cells,
defined on the basis of surface marker expression (CD30+, CD25+, CD45RO+,
CD4+, CD3+), was identified as the major source of T-helper activity in
a pokeweed mitogen activated B-cell system (14). The spectrum of cytokine
production (IL-5high, IFN-g high, IL-2low) did not fit the classical Th-1
Th-2 pattern, resembling more closely the Th-0 cell. Recent advances in
flow cytometry permit the detection of multiple cytokines produced in single
cells. Studies in normal and helm-inth-infected subjects indicate that
CD27 can be used to resolve populations of CD4+ T cells which produce IL-4
plus IFN-g, versus IL-4 or IL-5 or IFN-g alone (15). Such methods may help
clarify the role of activated T cells in B-CLL (see below).
IMMUNOPATHOPHYSIOLOGY OF B-CLL
Significance of CD5+ expression
CD5 is a monomeric glycoprotein expressed on virtually
all T-cells and on a subset of B-cells. Although the function of CD5 in
B-cells has not been fully determined, it associates with the B-cell receptor
complex and serves as a substrate for receptor-induced tyrosine kinase
activity. Thus, CD5+ is thought to have the potential to moderate signals
delivered by the B-cell receptor (44). Its natural ligand, the C
type lectin CD72 (45) is constitutively expressed on B-cells, giving rise
to the possibility of homotypic interactions between B-cells. Antibodies
directed against CD5 can be costimulatory in culture, although it is unclear
to what extent this mimics interactions with the natural ligand. The relative
scarcity of CD5+ peripheral B-cells in healthy adults (<30% of normal
peripheral B-cells are CD5+), their abundance in cord blood and lymph node
follicles as well as their association with autoimmune diseases and B-cell
malignancies have lead to conflicting interpretations concerning the significance
of CD5 expression on B-cells. CD5+ B-cells have been proposed to comprise
a separate B-cell lineage (16), or alternatively a stage of maturation
(17) or a subpopulation with suppresser activity (18). CD5+ B-cells have
been characterized as being particularly responsive to IL-5; their repertoire
of V H and VL usage has been reported to be restricted and prone to expression
of autoantibodies primarily restricted to the IgM isotype. The functional
significance of CD5 expression is particularly important in CLL, since
the great majority of B-CLL clones are CD5+. However, the results of a
recent report indicate that functional assumptions based on the expression
of the CD5+ phenotype must be viewed with caution (19). In contrast to
CD5+ cells in the lymph node, which are sIgM+, CD5+ B-cells isolated from
the peripheral blood of healthy subjects express levels of IgG and IgA
comparable to their CD5 negative counterparts. Further, CD5 negative cells
rapidly and transiently became CD5+ upon exposure to PMA and anti-CD3 activated
T-cells. In cell separation experiments, the CD5-B-cells, which became
CD5+ in culture, produced the greatest amounts of immunoglobulin. CD5+
and negative B-cells produced comparable levels of autoantibody. Taken
together with the reports cited above, it is clear that CD5 can be expressed
on B-cells displaying a broad spectrum of activities and ranging widely
in maturational status. According to this interpretation, CD5 expression
on B-cells may be analogous to the expression of certain T-cell “activation
markers.” For example, CD38 is constitutively expressed on late thymocytes
but is also inducible during activation of mature memory T-cells. Like
CD5, its expression is not restricted to cycling cells and in fact is detected
on a proportion of small resting T-cells as well. In B-CLL and normal mantle
zone B-cells, the expression of CD5 on predominantly small resting cells
may reflect their history of activation and proliferation. Thus CD5 may
reveal more about the recent experience of a B-cell than it does about
its pedigree or maturational state. Accordingly, it is not surprising that
a variety of pathologic processes involving B-cell proliferation or activation
have been associated with CD5 expression.
The specificity of B-CLL surface immunoglobulin
B-CLL hybridomas have been successfully made by
a number of laboratories (20, 21). Productive hybridomas have been isolated
at high frequency using a variety of murine myeloma fusion partners. Virtually
all primary hybridomas produced IgM monoclonal antibody (MAb) which were
remarkably similar between patients. Many were broadly reactive, using
a restricted
set of Ig variable region heavy and light chains encoded by germline
or minimally mutated germline genes (22), and shared cross reactive idiotypes
with antibodies associated with rheumatoid arthritis. In a very detailed
analysis of the complete heavy and light chain sequences of seven B-CLL
hybridomas, three displaying polyreactive binding used V H 4 family members
and three which displayed rheumatoid factor activity expressed V H 1 family
genes (23). Kipps has suggested that normal B-cells expressing such
autoantibodies may be perpetually stimulated, thereby increasing the opportunity
for malignant transformation into CLL, or alternatively that anti-self-reactivity
may enhance the survival of a B-cell clone a transformation event (39).
In the discussion below we will entertain the hypothesis that these polyreactive
autoantibodies may interact with signaling and/or adhesion molecules on
T-lymphocytes.
T-cell expansion in B-CLL
Normally B-cells comprise a relatively small proportion
of circulating lymphocytes. Their clonal expansion in B-CLL raises their
proportion such that T-cells appear as a minor subpopulation. However,
examination of absolute T-lymphocyte counts (CD3+ cells/mm 3 ) revealed
an increase in T-cells as well (1.9-fold higher than control subjects in
a series of 10 Rai stage 0 patients and controls, p = 0.004, Student's
t-test.). This highly significant increase in T-cells was masked by the
overwhelming increase in B-cells when proportion rather than absolute number
was considered. We (24) and others (25) have examined expression of activation
markers on T cells from patients with B-CLL. One of the most intriguing
findings in our study of stage 0 B-CLL patients was that 10-60% of cells
falling within the high forward scatter/low side scatter region (which
encompasses large atypical lymphocytes and also lymphocyte clusters) were
actually CD3+ T-cells. Because of these unique light scatter properties,
we were able to compare cells falling within this region with small lymphocytes
from the same individuals. Large atypical T-cells did not comprise a discernible
population in young healthy control subjects and were only occasionally
detected as a minor population in control subjects who were age-matched
to the patients. We compared T-cell differentiation and activation markers
on large/atypical- and small-lymphocyte light scatter populations within
10 individuals with Rai stage 0 B-CLL, and between the total lymphocyte
scatter population of 10 healthy control subjects. No differences were
observed between markers on the small lymphocyte population of the B-CLL
group and the total lymphocytes of the healthy controls. In contrast, most
CD4+ large atypical T-cells were CD45RO+ (77% vs. 27%, large vs. small
lymphocyte). Significant subsets within the CD4+ population were CD45RO+/CD29high
(77% vs. 25%, Figure 1) and CD25+/CD38dim (32% vs. 16%). Quantitative cytokine
determinations in isolated large lymphocytes from one CLL patient (Table
2) revealed a robust T-helper response. The observed increase in IL-2 production
(23-fold over control response) has recently been attributed to the effect
of B-cells as APC and could be duplicated when T-cells from healthy subjects
were exposed to normal B-cell APC (26).
Anti-T Cell Agents and B-CLL Therapy
The unique natural history of B-CLL makes its treatment
problematic. Early disease (Rai stage 0, Binet stage A) is not treated
until it progresses. Advanced disease and rapidly progressing early
disease are treated, traditionally with alkylating agents or combination
chemotherapy, and more recently, with deoxypurine analogs. The deoxypurine
analogues fludarabine, 2-chlorodeoxyadenosine, and pentostatin are gaining
acceptance as first line agents (27). The purine analogs have potent effects
against normal T cells as well as leukemic B-cells, owing to the high activity
of adenosine deaminase in lymphocytes. Cyclophosphamide, prednisone,
and methotrexate, three other agents used in CLL regimens, exert immunosuppressive
effects on T as well as B lymphocytes. In fact, one of the limiting toxicities
of fludarabine/prednisone combination therapy has been opportunistic infections
associated with prolonged severe depression of CD4+ T cell counts (28).
Opportunistic infection and depressed CD4 counts were also seen in patients
treated for 16 weeks with the humanized anti-CD52 antibody Campath 1-H
(40). Campath 1-H targets CD52 on both T and B lymphocytes. Finally, Cyclosporine
(CsA), a T-cell immunosuppressive agent with poorly characterized anti-B-cell
activity, has been successfully used to treat autoimmune disorders such
as pure red cell aplasia occurring in conjunction with B-CLL (41). We know
of three cases in which treatment with CsA (unusually combination with
glucocorticoids) resulted not only in an improvement in erythropoiesis,
but in a marked decrease in the number of circulating leukemic B-cells
as well. An example from our own center is shown in Figure 2. Although
several other clinical anecdotes reporting beneficial effects of CsA have
been published, its use as a primary therapeutic agent for CLL is far from
accepted. In a recent series of 5 patients prospectively treated with CsA,
a Belgian center reported a marginal anti-tumor response and an unacceptable
worsening of treatment related immunosuppression (42). That the benefits
of anti-T cell directed CsA therapy were short lived (B-cell counts increased
on discontinuation of CsA, Figure 2), may imply an inhibitory as well as
stimulatory role for T-cells.
It should be noted that regardless of the regimen,
chemotherapy rarely, if ever, results in the cure of B-CLL. With the exception
of bone marrow transplantation, which has resulted in elimination of the
malignant clone as evidenced by negative PCR (43), but has limited followup,
even the best of today’s therapies are ultimately ineffective. Interestingly,
BMT provides not only the advantage of dose intensive therapy, but of complete
ablation of the T as well as B-cell compartment.
Taken together, these data strongly support the
notion that agents with anti-T-cell activity may indeed interrupt T-cell/B-cell
interactions which support the growth of the B-cell neoplasm. They also
sound cautionary notes: 1) that anti-T-cell agents which are relatively
well tolerated in the treatment of other conditions may have unacceptable
toxicity in CLL; one of the major consequences of the extensive outgrowth
of the neoplastic B-cell clone may be interference with T-cell regenerative
capacity following massive insults, such as those delivered by T-cell toxic
agents, 2) That nonspecific ablation of the T-cell compartment may remove
anti-leukemic as well as stimulatory populations. The identification
of targets which interfere with the delivery of exogenous growth and survival
signals to the B-CLL clone, without causing undue injury to the T-cell
compartment may be particularly useful in the development of new therapies.
Potential Roles of T-cells in B-CLL
From the evidence presented above, it is clear that
T cells play an, as yet, undefined role in B-CLL. The three most obvious
answers to the question “What are activated T-cells doing in a B-cell leukemia?”
are: 1) They are mediators of immune surveillance, doing their best to
keep a B-cell malignancy in check; 2) They are passively swept along by
a dysregulated B-cell neoplasm
that acts as both antigen presenter (26) and cytokine source (30);
or 3) As in normal T/B interactions, helper T-cells are in the driver's
seat, promoting B-CLL growth by providing the contact dependent and cytokine
mediated signals described above. The first hypothesis is of potential
importance, because if correct, it provides an avenue for therapeutic intervention
through augmentation of a preexisting anti-tumor response. Likewise, the
notion that T-cells are polyclonally activated by the B-cell neoplasm could
explain antibody mediated autoimmune processes, such as anemia and thrombocytopenia
which frequently develop in B-CLL. These are otherwise difficult to explain,
since the specificity’s of the autoantibodies are different from that of
the B-CLL. Indiscriminate T-cell activation could have the disastrous
consequence of inducing antibody expression in previously silent autoreactive
B-cell clones. Finally, the third answer opens the possibility that
B-CLL itself is an autoimmune process, resulting from a short circuit in
the normal lines of T-B communication.
B-CLL AS A SHORT CIRCUIT IN T-CELL/B-CELL
INTERACTION: A HYPOTHESIS
Any attempt to reconcile this hypothesis with the
observed natural history of B-CLL must take into account the clonal nature
of the disease and the failure of B-CLL cells to progress beyond the sIg
low state. Since every member of the B-CLL clone expresses surface immunoglobulin
of the same specificity, it is conceivable that this binding specificity
itself confers the selective
advantage that results in clonal outgrowth. Of course, it must also
be recognized that any B-cell mutation resulting in growth autonomy would
also show clonal immunoglobulin expression, providing that the transforming
event occurred subsequent to Ig gene rearrangement. As reviewed above,
the majority of stage 0 B-CLL are without evident chromosomal abnormalities;
when abnormalities are observed, they are diverse and are an indicator
of poor prognosis. Entertaining the unconventional hypothesis that
the CLL B-cell starts off life as a “normal” B-cell with an inopportune
specificity, we can postulate at least three experimentally testable mechanisms
that could lead to a privileged relationship with helper T-cells.
From least to most involved they are:
1) Preferential binding of CLL B-cells to activated
T-cells (Figure 3): B-CLL sIg binds to a surface determinant expressed
on activated, but not resting, T-cells. T-cells activated by irrelevant
antigens are physically captured by B-CLL cells through immunoglobulin
mediated binding in conjunction with other low affinity membrane-membrane
interactions. Once bound, B-CLL cells are stimulated by interaction with
CD40L and cytokines (eg, IL-4, IL-5), expressed by the activated T-cell.
B-CLL cells, in turn, back-stimulate the T-cells with equally nonspecific
signals (eg, B7). Yellin and colleagues have demonstrated that the cell
line Jurkat D1.1, which constitutively expresses CD40L, induces expression
of CD80 (B7.1) on resting normal and CLL B-cells (31). These findings support
our short circuit hypothesis, since upregulation of CD80 (CD28 ligand)
on B-cells renders them competent to present antigen to T-cells. In addition
to driving proliferation, activated T-cells can also provide anti-apoptotic
signals to B-cells through CD40L (32) and IFN-g (37). According to
this scenario, any event initiating T-cell activation (eg, immunization,
infection), would trigger a sympathetic increase in B-CLL cells as well.
This hypothesis is not strictly dependent on sIg specificity as the preferential
binding to activated T cells could be mediated by the coordinated expression
of conventional adhesion molecules on the B-CLL clone.
2) Mitogenic hypothesis (Figure 4): B-CLL sIg provides
an activation signal to resting T-lymphocytes by binding public domains
of the TCR (ie, like a superantigen), or more likely, to structures which
provide costimulatory signals (eg, CD2, CD28). This interaction increases
the probability that a random T-cell in proximity to a B-CLL cell will
undergo activation. Since CD40L expression on the T-cell is typically rapid
and short lived, this would give the B-CLL cell the advantage of being
in the right place at the right time when T-activation is initiated. As
in hypothesis 1 above, once activated, the B-CLL cell would initiate a
bi-directional paracrine loop by back-stimulating the activated T-cell
or its resting neighbors.
3) Paired clone hypothesis (Figure 5): This scenario
is a special case of hypothesis 2, in which a particular T-cell clone or
clones recognize the B-CLL idiotype as antigen (or vice versa). Since B-cells
can also act as APCs, and favor selection of Th-2 over Th-1 (38), it is
likely that the B-CLL specific T-cell would provide back-stimulatory signals
to the B-CLL APC. This would provide another entry point into the T-Cell/B-CLL
paracrine loop. The recent finding of skewed TCR Vb expression in B-CLL
provides evidence in favor of this hypothesis (33), although our own results
on a series of 5 patients revealed that the majority of the presumably
clonally expanded T-cells were CD8+ rather than CD4+ (34). This hypothesis
bears some analogy with the emerging picture of the etiology of a particular
type of gastric lymphoma of the mucosa-associated lymphoid tissue (MALT)
in which both clonal T and B lymphocytes have been detected (35). In some
instances the origin of MALT lymphoma has been attributed to an aberrant
T cell-dependent B-cell response to antigens present on an infectious agent,
Helicobacter pylori (see Chapter 8) (36).
The hypotheses presented above are not necessarily
mutually exclusive with those that envision a protective role for T-cells,
nor those that predict other autoimmune consequences of aberrant T cell
activation. What they have in common is the idea of a self-perpetuating
bi-directional stimulatory short circuit between T- and B-lymphocytes that
gives the B-CLL clone a survival advantage but does not allow it to progress
beyond the sIg low stage of development. It is not difficult to imagine
how, over the course of months, years or decades, chronic stimulation of
a single B-cell clone results in the emergence of mutant lines with less
stringent growth requirements. If T cells do in fact play such a role in
the natural history of B-CLL, it may be possible to disrupt the disease
process by targeting T cells or the signals that they provide.
ACKNOWLEDGMENTS
This work was supported by grant RO 1 CA44887 from
the National Institutes of Health. Dr. Donnenberg is the recipient of a
Carter-Wallace fellowship for AIDS research. The authors would like to
thank Drs. Arnold Meisler, Margaret Ragni, Delynne Myers, Witold B. Rybka
and Edward D. Ball for obtaining patient specimens and clinical data, and
Tim Patton, E. Michael
Meyer and Deborah Griffin for their expert technical assistance.
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