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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-03-0671.
IMMUNOBIOLOGY
From the Molecular Medicine Unit, The University of
Leeds, St James's University Hospital, United Kingdom;
Rheumatology and Rehabilitation Research Unit, The University of Leeds,
United Kingdom; Department of Rheumatology, Leiden
University Medical Centre, The Netherlands; and National
Blood Transfusion Service, Seacroft Hospital, Leeds, United
Kingdom.
Rheumatoid arthritis (RA) is a chronic, inflammatory disease of the
synovium of uncertain pathogenesis. A number of phenotypic and
functional T-cell defects have been described in RA, including abnormal
clonal expansions and suppressed proliferative responses, which suggest
a defect in T-cell differentiation. Here, we show that RA patients
possess fewer naive CD4+ T cells than healthy controls.
Furthermore, a smaller proportion of these cells contains a T-cell
receptor excision circle (TREC). Patients with RA also have unusual
populations of T cells. These include immature cells characterized as
CD45RBbrightCD45RA+CD62L Rheumatoid arthritis (RA) is a chronic,
inflammatory disease of the synovium whose pathogenesis is uncertain. A
number of features, such as major histocompatibility complex (MHC)
association,1 presence of circulating
autoantibodies,2 and infiltration of synovium with
activated lymphocytes,3 suggest an autoimmune diathesis,
though there are competing theories.4 Furthermore, RA T
cells are hyporesponsive to stimulation and share a number of features
with anergic T cells,5-7 and RA patients are clinically immunosuppressed. They have an excess of infections and malignancies of
the immune system.8,9 Additionally, unusual T-cell
expansions have been documented in RA patients10,11 along
with distortion of the naive T-cell repertoire.12,13 These
defects suggest abnormal T-cell development or differentiation in RA
that could underlie autoimmunity because inappropriate development and
maturation of lymphocytes may bypass tolerogenic mechanisms.
Evidence exists for defective T-cell reconstitution in RA patients with
therapy-induced lymphopenia. Patients undergoing autologous stem cell
transplantation (ASCT) retained CD4+ lymphopenia for more
than 12 months of follow-up.14,15 Furthermore, patients
who underwent lymphocytotoxic monoclonal antibody therapy did not
experience replenishment of their CD4+ and CD8+
T-cell compartments, even when studied 7 years after a brief course of
therapy.16 This is in contrast to what happens in patients
with hematologic malignancies or solid tumors, most of whom have
reconstituted T-cell compartments within 1 year of lymphoablative therapy.17-19 Age-related thymic involution may partly
explain this disparity, but, until recently, the best available
surrogate measures of thymic function were numbers of circulating naive T cells and radiographic estimation of thymic size.20 The
development of techniques for measuring T-cell receptor excision
circles (TRECs) has now provided a novel marker. When T cells rearrange
their antigen-specific receptors, certain DNA recombination events must take place.21 These involve the excision of small circles
of DNA that remain within the cells as episomes. The formation of the
TCR- Numerous dynamic processes also influence TREC measurements. For
example, the TREC content of naive T cells is influenced by thymic
activity on the one hand, proliferation of cells within that subset and
differentiation of TREC-containing cells into a more mature phenotype
on the other. Thus, in a recent analysis of HIV patients, the
proliferation and differentiation of T cells, but not thymic function,
were reported to be the major determinants of the TREC content of naive
T cells.27 Similarly, when TRECs were measured in patients
with RA compared with age-matched control subjects, a significant
deficit was demonstrated.28 This might have reflected
diminished thymic output, but there was also evidence of enhanced
lymphocyte proliferation that might have diluted TRECs.
Defects of thymic function and T-cell differentiation could clearly
underlie some of the characteristic immunologic phenomena seen in RA
patients. Thus, impaired thymic activity could contribute to the
reconstitution defect after lymphodepleting therapies. Similarly,
differentiation defects may result in unusual clonal expansions. A
better understanding of T-cell dynamics in RA should help to address
these possibilities. In this paper we confirm that lymphocytes
proliferate abnormally in RA patients. This contributes to reduced
TRECs in peripheral blood and gives rise to T cells of atypical
phenotype. Although inflammation provides a proliferative stimulus,
similar abnormalities appear to be present at disease onset. We suggest
that abnormal T-cell dynamics may contribute to autoreactivity in
persons in whom RA eventually develops.
Patients and healthy controls
T-cell subset separation
Real-time polymerase chain reaction quantification of TRECs DNA was extracted from lymphocytes using standard proteinase K digestion followed by phenol/chloroform extraction from either total CD4+ populations after magnetic separation or from naive cells after cell sorting. We performed SYBR-green real-time polymerase chain reaction (PCR) based on the coding TREC sequence using an ABI 7700 Sequence Detection System (PE Applied Biosystems, Warrington, United Kingdom). We designed primers to amplify a DNA fragment of 83 bp across the remaining recombination sequence rec/ alpha (F-CAC CTC TGG GCT ACG TGC TAG and R-GAA CAC ATG CTG AGG TTT
AAA GAG AAT). Optimization was performed according to the
manufacturer's instructions using DNA extracted from umbilical cord
blood mononuclear cells and a cloned target inserted into a TA-cloning
plasmid (Invitrogen, Leek, The Netherlands). This method quantitated
TREC molecules per microgram DNA. We subsequently developed a method
for the quantification of TRECs based on TREC copy number relative to the GAPDH gene copy number. The latter was proportionate to
the number of cells analyzed per sample (F-AAC AGC GAC ACC CAT
CCT C and R-CAT ACC AGG AAA TGA GCT TGA CAA). This analysis provides a
final value that represents TREC DNA as a proportion of
GAPDH DNA, equivalent to the percentage of cells containing
a TREC (F.P. et al, manuscript submitted).
Proliferation assay CD4+ T cells were separated as above from 50 mL blood. Naive and atypical subsets were sorted under sterile conditions according to the expression of CD45RB, CD45RA, and CD62L. Cells were cultured in RPMI 1640 supplemented with penicillin/streptomycin, glutamine, and 10% human AB Rh-positive serum (Sigma-Aldrich, Poole, United Kingdom), and proliferation was assessed in response to phytohemagglutinin (PHA; 0.01-10 µg/mL; Sigma) or to anti-CD3 antibody (OKT3 0.01-1 µg/mL) plus or minus anti-CD28 (YTH913.12, 5 µg/mL) co-coated on plastic. Irradiated autologous CD4+ T-cell-depleted PBMCs were used as feeder cells in a 1:1 ratio to CD4+ T cells. Proliferation was quantified by the incorporation of 3H-thymidine (1 µCi/well [0.037 MBq/well]) after 5 days of culture.Statistical analysis Nonparametric tests were used throughout. The Mann-Whitney U test for 2 independent samples was used to compare healthy controls with RA patients. Spearman rank correlation coefficient was used to correlate 2 variables. Linear regression was used to seek dependency between clinical parameters and laboratory outcomes. The following variables were tested as predictors in linear regression analysis: age, sex, disease duration, CRP, current methotrexate therapy, current sulfasalazine therapy, and current corticosteroid use.
T-cell differentiation is distorted in patients with RA We initially compared the proportion of circulating CD4+ T cells expressing naive and memory surface markers in RA patients and in healthy controls. Controversy remains over the most reliable surface phenotype of naive T cells. Novel markers have recently been identified, such as the presence of CD103 or CCR7 and the lack of CD27,30-32 but no single marker may be specific. CCR7, for example, has also recently been identified on certain memory T-cell subsets.33 Traditionally, isoforms of the tyrosine phosphatase CD45 (RB, RA, and RO), along with expression of the lymph node homing receptor CD62L, have been used to distinguish naive from memory T cells. CD45RB is highly expressed by naive T cells and is gradually lost after antigenic exposure (bright dull), in parallel with an increase in CD45RO expression (negative dull bright).34 CD45RA and CD62L are also
expressed primarily by naive T cells, though they can be reexpressed at
a later stage of differentiation.30,33,35 We therefore
used these markers to examine T-cell maturity in our patient and
control populations (Figure 1).
Figure 1A illustrates flow cytometry data for a representative healthy
control (57 years old) and a patient with early RA (42 years old).
CD45RBbright populations are plotted in green, and
CD45RBdull populations are plotted in pink. CD45RO
expression is characterized as bright, intermediate, or negative,
whereas CD45RA and CD62L expression is positive or negative. In healthy
controls (upper panels), CD45RBbright CD45RA+
cells are also CD62L+ and CD45RO In view of these data, we analyzed the proportion of naive and memory
peripheral blood CD4+ T cells in a cross-section of healthy
controls and RA patients. In controls (Figure 1B, Table
2), the percentage of naive and memory
cells decreased and increased, respectively, with age. In RA patients
fewer naive T cells were present at all ages, though the proportion of
memory cells remained similar to that in healthy controls.
Frequency of TREC-containing T cells is reduced in RA patients The reduced number of naive T cells in patients with RA could have resulted from reduced thymic production or from accelerated differentiation or death. Recent thymic emigrants can be identified by the presence of a TREC,21,23 and the proportion of T cells containing a TREC provides an estimate of recent thymic activity. We developed an assay based on real-time PCR to provide an accurate measure of TRECs in peripheral blood. In healthy controls, there was a strong inverse correlation between age and TREC content of the peripheral blood CD4+ T-cell pool, reflecting the acknowledged decrease in thymic function with age. In RA patients a weak inverse relationship with age was still present, but TREC levels were lower than those in controls (Figure 2A, Table 2), irrespective of disease duration. These data confirm observations previously reported in RA patients.28
When we examined naive T-cell TREC content specifically, the inverse relationship between TREC content and age was lost (Figure 2B, Table 2). Fewer TRECs remained in RA patients, but there was greater variability and the distinction from healthy controls was less marked. There were fewer TRECs in the naive T cells of patients with established resistant RA than there were in patients with early disease (P = .005). Inflammation predicts the TREC content of naive T cells We applied linear regression to seek a clinical correlate of naive CD4+ T-cell TREC content. This analysis suggested a model in which the TREC content of naive CD4+ T cells could be predominantly explained by an inverse relationship with CRP. Figure 3A illustrates this relationship in a cross-section of RA patients, and Figure 3B illustrates it in an RA patient with relapsing and remitting disease who was followed up longitudinally for more than 2 years.
Atypical CD4+ T cells in RA patients are the progeny of naive T cells Assuming peripheral blood T cells mature and differentiate at a relatively constant rate during adult life, a gradual fall in thymic output will be reflected by a parallel reduction of total T-cell TREC content (Figure 2A).20,22,23,26 In contrast, provided intrathymic T-cell differentiation is invariant, the TREC content of naive T cells leaving the thymus should remain relatively constant with age. If this is the case (Figure 2B, healthy controls), the simplest explanation for reduced TRECs in naive T cells of RA patients is a dilutional effect of cell proliferation. If these cells also alter their surface phenotypes, this may account for the appearance of T cells of unusual phenotype in RA patients (Figure 1A).To seek evidence that atypical T cells derive from naive T cells, we
measured the TREC content of various CD4+ T-cell subsets in
3 healthy controls and 3 patients with early RA. Cells were sorted
according to their expression of CD45RB, RA, and CD62L following a
primary sort based on CD45RO expression. Five populations were isolated
from the healthy controls and 8 from the RA patients. The proportion of
T cells containing a TREC within each subset was then quantified. T
cells can only acquire TRECs within the thymus; they subsequently lose
them as they differentiate and expand. It follows that a TREC-poor
T-cell subset must be more mature than a TREC-rich T-cell subset and
that TREC content can be used to provide a surrogate marker of T-cell
ontogeny. In Figure 4, T-cell subset TREC
content is related to that of naive cells. In healthy controls, TRECs
are most abundant in naive T cells. They are next most
frequent in CD45RBbright CD45RA
These results support the hypothesis that there is abnormal,
inflammation-driven, T-cell proliferation and differentiation in RA
patients that results in the appearance of T-cell subsets of atypical
phenotype. Further support for the hypothesis is shown in Figure 3C,
which illustrates a positive correlation between the frequency of
atypical RO Atypical cells have a lower activation threshold than naive cells The role of CD45RO versus RA in T-cell activation is uncertain, but memory cells require less stimulation than naive cells to proliferate.36-38 The threshold necessary to activate naive T cells through their TCR is also lowered once they have been induced to proliferate by proinflammatory cytokines such as tumor necrosis factor- (TNF-) and interleukin-6
(IL-6).39,40 We therefore analyzed the response of naive
and atypical RBbright CD4+ T cells to mitogen
and TCR stimulation in 5 RA patients (Figure 5). CD4+ T cells were sorted
according to their expression of CD45RBbright
CD45RA+ CD62L+ CD45RO (naive) and
CD45RBbright CD45RA+ CD62L
CD45RO/bright (atypical) and were stimulated with PHA and
with anti-CD3 and CD28 antibodies. Atypical cells were more responsive
than naive cells to mitogen and TCR stimulation. Notably, they
proliferated strongly to CD3 plus CD28 but not to CD3 alone.
We have demonstrated a significant perturbation of T-cell dynamics
in RA. Patients had fewer naive T cells than controls, but they also
had T-cells of various atypical phenotypes (Figure 1). Additionally,
the TREC content of all T-cell subsets was lower in RA patients than in
controls (Figure 2 and Table 2). These data are readily explained by
abnormal naive T-cell proliferation and phenotypic differentiation,
though we cannot exclude an additional defect of thymic T-cell
production (see below). Furthermore, the predictive value of CRP
(Figures 3, 5) implicates inflammation as the driving force behind the
observed abnormalities. Together these results are consistent with a
model in which inflammatory stimuli promote the proliferation of naive
T cells in RA and their differentiation into subsets of atypical
phenotype. Recently, Koetz et al28 also demonstrated
reduced total TRECs in RA patients compared with healthy controls.
Interestingly, they showed a reduction in telomere length of patients'
naive (CD45RO With the aid of current knowledge of T-cell differentiation, we have
used TREC content to construct hypothetical maturation pathways for
healthy controls and RA patients (Figure
6). In healthy controls, a predominant
pathway leads to conventional memory cells (CD45RBdull
CD45RA
In RA patients, the pathway leading to conventional memory cells
appears intact. Atypical subsets appear to develop directly from naive
T cells. CD45RA expression is never terminated along this pathway,
despite the acquisition of CD45RO, giving rise to the large population
of CD45RA CD45RO double-positive cells in RA patients. Additionally,
central memory cells are not evident in RA patients but a further
atypical subset appears (CD45RBdull CD45RA Our data have implications for the pathogenesis of RA. Atypical cells
have a reduced threshold for activation (Figure 5) and premature loss
of surface CD62L (Figure 1), which may result in disordered migration
with the bypass of lymph nodes and the arrival at peripheral sites.
Under specific circumstances, such as tissue trauma or infection, this
could result in inappropriate autoreactivity. Consistent with this
hypothesis, synovial T cells in RA patients have recently been likened
to cytokine-activated T cells,42 and the latter have been
shown to elicit a proinflammatory response from
monocytes.43 Additionally, clonal expansion of unusual CD4+ T-cell subsets lacking CD28 and CD7 expression or
expressing CD57 have been reported in RA.10,11,44,45 In
particular autoreactive CD4+CD7 Proliferation and ultimate exhaustion of the naive repertoire could also contribute to the immunosuppression and T-cell hyporesponsiveness characteristic of RA, as previously suggested.47 We also observed an apparent loss of central memory cells in RA patients, which may be critical for efficient secondary immune responses.33 Additionally, inappropriate trafficking of antigen-inexperienced T-cells, with bypass of lymph nodes caused by the loss of CD62L expression, may, under some circumstances, promote anergy induction through nonprofessional antigen presentation. Through these mechanisms, the increased incidence of infections and immune malignancies in RA could be a further consequence of the abnormalities that we have documented. Because these abnormalities are inflammation driven, it could be argued that they are secondary and of doubtful pathogenic significance. Their presence in patients with symptoms of recent onset, however, suggests otherwise, though this could reflect a significant preclinical phase of RA.48 On the other hand, oligoclonal T-cell expansions have been described in the first-degree relatives of RA patients, suggestive of a primary T-cell proliferative defect.49 Dysregulated T-cell proliferation may, therefore, represent a critical pathogenetic event in RA. Our results also reinforce the concept that TREC measurements
reflect dynamic processes. Thus, though originally defined as a
surrogate measure of thymic activity, T-cell proliferation also has a
significant influence on peripheral blood TREC concentrations. Indeed,
using mathematical modeling, a cogent argument has been made that TREC
variability in HIV patients is better explained by changes in
peripheral T-cell division rates than by an effect on thymic
function.27 Similarly, the proliferative abnormalities we
have documented prevent us from making a definitive statement about
thymic activity in RA patients. Notwithstanding this caveat, RA may
well have a suppressive effect on thymic function. For example, several
of the cytokines associated with active RA In summary, we have confirmed and illuminated some of the T-cell differentiation defects in RA. In particular we have demonstrated that RA patients have unusual, hyperresponsive peripheral blood T-cell subsets. Inflammation appears to drive the appearance of these cells, though they are already present in patients with recent-onset disease. Thus, a primary defect may exist, and we have argued how the inappropriate proliferation of T cells could contribute to RA-associated immunosuppression and disease pathogenesis. Last, our data reinforce the importance of early and aggressive therapy for RA. Although T-cell abnormalities may predate clinical signs and symptoms, they appear to be perpetuated by inflammation. Therefore, the control of inflammation, particularly through the use of cytokine blockade, should minimize dysregulation of proliferation.
We thank Professor Alan Tennant for his assistance with statistical analysis and Professor Herman Waldmann for the supply of YHT913-12 antibody.
Submitted March 6, 2002; accepted July 18, 2002.
Prepublished online as Blood First Edition Paper, August 8, 2002; DOI 10.1182/blood-2002-03-0671.
Supported by the Arthritis Research Campaign (P0566), The United Kingdom Medical Research Council, the Dutch Arthritis Association (NR99-1-301), and the Candlelighters Trust.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: John D. Isaacs, Molecular Medicine Unit, Clinical Sciences Bldg, St James's University Hospital, Leeds, LS9 7TF, United Kingdom; e-mail: rrrjdi{at}leeds.ac.uk.
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Top
Abstract
Introduction
indicate healthy controls; 
, patients with early
RA; 
, patients with resistant RA. Statistical analysis: controls,
age versus naive T-cell proportion, r = 
0.930,
P < .0001; age versus memory T-cell proportion,
r = +0.865, P < .0001. RA patients (both
groups combined): age versus naive T-cell proportion,
r = 
CD45RBdull CD45RA+
CD45RObright (white arrow; also known as
CD62L
) and TREC content of naive
(CD45RBbright CD45RA+ CD62L+)
CD4+ T cells (
, and oncostatin M