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+ T Cells and Homeostatic T Cell Proliferation in Y-Chromosome-Associated Murine Lupus1
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain gene-deleted BXSB mice to directly examine the role of
+ T cells and the mode by which Yaa
promotes disease in this strain. All disease parameters, including
hypergammaglobulinemia, autoantibody production, glomerulonephritis,
and the unique monocytosis of BXSB males, were severely reduced or
absent in the + T cell-deficient mice. Adoptively
transferred CD4+ T cells of either male or female BXSB
origin showed equal homeostatic proliferation in + T
cell-deficient male recipients. Moreover, deficient male mice
eventually developed equally severe lupus-like disease after adoptive
transfer and homeostatic expansion of T cells from wild-type BXSB males
or females. The results directly demonstrate that the
Yaa-mediated disease requires + T
cells that are not, in themselves, abnormal in either composition or
properties, but are engaged by a Yaa-encoded abnormality
in a non-T cell component. In addition, homeostatic anti-self
proliferation of mature T cells derived from a small number of
precursors can induce systemic autoimmunity in an appropriate
background. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gene, and thus of
+-expressing T cells, led to a significant,
but incomplete, disease amelioration (2). However, disease
was almost completely eliminated upon deletion of both TCR
and -
genes, and thus of +
and 
+ T cells (3). For two
other spontaneous mouse models of lupus, (NZB x
NZW)F1 and BXSB, studies have only indirectly
implicated a role for T cells in disease pathogenesis. In (NZB x
NZW)F1 mice, treatment with Abs to Thy1.2
(4), CD4 (5), MHC class II (6),
and B7 (7) or treatment with CTLA4Ig alone
(8) or in combination with anti-CD40 ligand
(9) resulted in significant disease reduction. Initial
efforts with anti-Thy1.2 Ab treatment of BXSB mice were confounded
by an unexplained anaphylactic reaction (4), but
subsequent experiments with anti-CD4 Ab (10) or
CTLA4Ig (11) also reduced disease incidence and
severity.
Despite many common characteristics, the three major mouse models of
lupus exhibit unique histologic and serologic manifestations as well as
unique disease accelerators. These accelerators include female hormones
in New Zealand mice, the Faslpr mutation
in MRL-Faslpr mice, and a
Y-chromosome-associated accelerator of autoimmunity, termed
Yaa,3 in
BXSB mice that remains to be identified (reviewed in Ref.
1). Radiation bone marrow chimera experiments with T and B
cells of Yaa and non-Yaa origins showed that the
determining factor for autoantibody production in BXSB mice was the
presence of the Yaa gene in B, but not T cells (12, 13). Other studies have also demonstrated that Yaa
primarily increases immune responses to weakly immunogenic Ags
(14). Therefore, it was hypothesized that Yaa
promotes autoimmunity by enhancing Ag presentation (for example,
through increased peptide presentation or increased costimulation),
which then facilitates the engagement of otherwise quiescent,
low-affinity, self-reactive T cells (12, 13). Further
evidence for MHC-dependent T cell engagement in the BXSB disease has
been suggested by the inhibitory effects of high I-E transgenic
expression in this H-2b mouse (15).
This effect appears to be due to competitive inhibition of autoantigen
presentation by peptide fragments from processed I-E bound
effectively to H-2b class II MHC molecules.
We initially generated congenic TCR-/- BXSB
mice to directly determine whether + T
cells are required in the male BXSB disease and found that such mice
were indeed free of disease. We then performed adoptive transfers of
small numbers of wild-type (WT) Yaa+ or
Yaa- mature CD3+ T
cells to determine whether proliferation of these cells in the
lymphopenic Yaa+ hosts were equally capable
of inducing the full disease spectrum and found that this was the case.
Hence, the Yaa gene defect does not modify thymic selection
or properties of T cells, but, rather, induces their excessive
activation through a non-T cell component.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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129/Sv x C57BL/6 TCR-/- mice
were obtained from M. J. Owen (Imperial Cancer Research Fund,
London, U.K.). BXSB TCR-/- mice were
generated by six backcrosses of the 129 x C57BL/6
TCR-/- mice to the BXSB strain, followed by
final intercrossing of heterozygous BXSB
TCR+/- offspring. Control
TCR+/+ and homozygously deleted
TCR-/- male BXSB littermates were analyzed
in this study. Genotyping for the TCR deletion was performed by PCR
detection of the neo gene, followed by confirmation of the homozygous
deletion with anti-CD3 staining and FACS analysis
(16). Mice were maintained under specific pathogen-free
conditions, and procedures were performed according to guidelines of
the institutional animal research committee.
Pathology
Mutant and control littermates were bled bimonthly and followed for survival until the termination of the experiment. Blood urea nitrogen was measured using AZOSTIX strips (Bayer, Elkhart, IN) according to the manufacturer and was graded on a 1–4 scale (5–90 mg/dl). Histologic examination of periodic-acid Schiff-stained kidneys was performed in a blind manner at 5 mo of age, and the severity of glomerulonephritis (GN) was defined on a scale of 0–4+ (16). OCT (Miles, Elkhart, IN)-embedded snap-frozen kidneys were thin sectioned, air dried, fixed in ice-cold acetone, and blocked with 10% horse serum in PBS. Sections were then incubated with anti-IgG-FITC (Vector Laboratories), and deposit intensity was scored as previously described (17).
Serologic analysis
IgG and autoantibody levels were detected by ELISA as previously described (17). Briefly, IgG in serial dilutions of sera was captured on 96-well plates coated with either the Fc-specific F(ab')2 of goat anti-mouse IgG (5 µg/ml; Jackson ImmunoResearch, West Grove, PA) or mouse chromatin (3.5 µg/ml). Bound IgG subclasses were measured using alkaline phosphatase-conjugated goat anti-mouse IgG subclass-specific Abs (Caltag, Burlingame, CA). Standard curves for each subclass were generated using calibrated mouse serum (Binding Site, Birmingham, U.K.).
FACS analysis
Splenocytes and PBMC were stained with various combinations of
Abs to TCR -chain, CD3, CD4, CD8, CD19, CD44, and/or CD11b
(Mac-1+; BD PharMingen, La Jolla, CA). FACS data
were acquired (>10,000 events) on a FACSort and were analyzed with
CellQuest analysis software (BD Biosciences, Mountain View,
CA).
Adoptive transfers
To assess in vivo proliferative responses, two groups (nine mice
per group) of + T cell-deficient young male
BXSB mice were injected i.v. with 2 x 106
highly purified (95.5% purity) CD4+ lymph node
(LN) cells from either male or female young BXSB mice (18)
that were stained with the intracellular fluorescent dye CFSE
(Molecular Probes, Eugene, OR), as previously described
(19). Unlabeled donor T cells were analyzed by flow
cytometry before injection. Both male and female T cells were <15%
CD44high, <15% CD69+,
<10% CD25+, and >85%
CD45RBhigh, a phenotype typical of T cells from
young unmanipulated BXSB mice. Three mice from each group were
sacrificed at 2, 5, and 21 days after transfer, and patterns of cell
division as well as total donor T cells (Thy
1.2+, CD4+) in LN
(axillary, inguinal, cervical, mesenteric) and spleen were determined
by FACS.
To assess disease induction, young (2-mo-old)
+ T cell-deficient male BXSB mice were
transfused with 4–5 x 106 FACS-sorted
CD3+ LN cells from 2-mo-old BXSB WT male or
female donors (10–12 mice/group) and followed for up to 9 mo of age,
and survivors were sacrificed for serologic, cellular, and histologic
assessments. A cohort of 20 control WT male BXSB mice was followed
in parallel for survival, and an additional 6 were sacrificed at 4 mo
for serologic, cellular, and histologic comparisons.
Statistics
Student’s t test was used for group mean comparisons, and survival was analyzed by the Kaplan-Meier method with comparisons by a log rank test. A value of p < 0.05 was considered to be significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine to what extent + T cells
are required for the development of lupus-like disease in the BXSB
model, BXSB mice deficient in the TCR -chain were generated, and the
severity of autoimmune manifestations in male
(Yaa+) TCR-/-
and littermate TCR+/+ controls was compared.
The absence of detectable + T cells in the
TCR-/- mice was confirmed by flow cytometry
using Abs to the TCR -chain. Mice were followed for survival for 9
mo, well beyond the life expectancy of BXSB males (1).
Strikingly, the lack of TCR+ cells resulted
in a dramatic increase in survival (Fig. 1
). Control BXSB males exhibited 50%
mortality at 5.3 mo and 100% mortality by 6.5 mo, while BXSB
TCR-/- male mice were all alive at 9 mo
(p < 0.0001). Notably, the mortality rate of
the littermate controls was similar to that of our WT BXSB colony,
indicating that the congenic line contained the major BXSB lupus
susceptibility genes.
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Serum polyclonal IgG levels were determined in
TCR-/- and TCR+/+
littermates at 5 mo of age. Although the controls exhibited typical
hypergammaglobulinemia, all IgG subclasses were significantly lower in
TCR-/- mice (p <
0.001), resulting in a >9-fold reduction of total serum IgG (Fig. 2A). Nonetheless, the IgG
levels and subclass distributions in these mutant mice were similar to
those commonly found in normal genetic background mice, an observation
consistent with reports indicating considerable class switching in the
absence of + T cells (20). Our
previous studies have shown that the autoantibody response to native
chromatin in lupus-predisposed strains, including BXSB, generally
preceded the appearance of autoantibodies against chromatin
subcomponents, such as dsDNA and histones (21). To
evaluate disease progression in the groups studied, we determined
antichromatin titers at 5 mo of age and detected high levels,
predominantly of the IgG2a subclass, in TCR+/+
littermates, while such autoantibodies were virtually absent in the
deficient mice (Fig. 2B).
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Weights and cellular composition of spleen and lymph nodes were
also analyzed (Table I). As expected,
there was a significant reduction in the weights of both organs in the
TCR-/- mice compared with controls
(p < 0.05) with, on the average, a 10-fold
decrease in LN and a 2-fold decrease in spleens. Similarly, deficient
mice were devoid of T cells, while, as previously reported (22, 23), the controls showed a large proportion of
CD44high activated/memory phenotype T cells
(Table I). In TCR-/- mice, however, there
was an incremental increase in the frequency of
CD19+ B cells, probably due to the absence of
+ T cells.
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Previous studies have shown the accumulation of a peculiar
Mac-1+ MHC class
II- monocyte population in the peripheral blood
of male, but not female, BXSB mice (24). To determine
whether this monocytosis is T dependent, we analyzed
Mac-1+ expression in PBMC of 5-mo-old mice (Table I
). Although control TCR+/+ mice exhibited the
typical expansions of Mac-1+-expressing cells
(21.2%), this population was significantly reduced (8.9%) in
TCR-/- mice (p <
0.01). The reduction in absolute numbers of these cells is probably
more severe than the indicated drop in percentage suggests, since
+ T cells are not present in the
deficient mice.
Renal histology
Kidney weights, GN scores, and blood urea nitrogen levels were
reduced (p < 0.05) in 5-mo-old BXSB
TCR-/- mice compared with
TCR+/+ controls (Table II). Control BXSB male mice exhibited
typical glomerular pathology, including extended glomeruli, sclerosis
of glomerular capillary walls, and heavy periodic acid-Schiff-positive
material in the mesangial matrix (Fig. 3). Hypercellularity of the mesangium and
the presence of both mononuclear and polymorphonuclear cells were also
noted in the control mice, as were heavy glomerular IgG immune deposits
in the mesangium and capillary walls. All these parameters were
considerably reduced in TCR-/- mice
(Fig. 3).
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Several recent studies have shown that small numbers of T cells
transferred into lymphopenic hosts proliferate extensively to
reconstitute the original lymphocyte pool (reviewed in Refs.
25, 26, 27). This proliferation appears to be mediated by
recognition of self-MHC/peptide ligands. Therefore, male mice deficient
in + T cells, and thus lymphopenic, were
adoptively transferred with small numbers of CFSE-stained
CD4+ LN cells from WT male and female donors to
determine the degree of homeostatic proliferation. In agreement with
previous studies (18), no proliferation was detected on
day 2 after transfer, since CFSE-stained cells were confined to a
single peak on the far right of the histogram (data not shown).
Thereafter, both WT male and female CD4+ T cells
transferred into + T cell-deficient male
mice proliferated extensively and equally, thereby leading to reduced
CFSE intensity in 87–89% of donor cells on day 5 and 96% on day 21
after transfer (Fig. 4A).
Consequently, enumeration of donor T cells (Thy
1.2+, CD4+) at these two
time points showed a nearly identical recovery regardless of donor
gender (Fig. 4B).
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Since + T cell-deficient mice were
free of disease and mature T cells transferred into lymphopenic hosts
homeostatically expanded, we performed adoptive transfers of small
numbers (4–5 x 106) of WT male or female
CD3+ LN cells into male
+ T cell-deficient mice to determine
whether T cell origin affects disease reconstitution in the lymphopenic
male BXSB background.
Male recipients of either male or female T cells exhibited equal
mortality rates, with 
50% of the animals dead at 9 mo of age, or 7
mo after transfer, the latest point of observation (Fig. 5). This mortality rate is delayed 2
mo compared with an unmanipulated cohort of control WT male BXSB mice,
which may be explained by the time required for the small number of
transfused cells to expand sufficiently. Serologic analyses showed that
increases in polyclonal IgG (Fig. 6A) and antichromatin (Fig. 6B) subclasses of male + T
cell-deficient recipients of either male or female WT T cells were
equal and approximated those of the unmanipulated WT mice. Similarly,
spleen and LN weights and cellular compositions, including high
percentages of activated/memory phenotype
CD4+CD44high and
CD8+CD44high cells were
equal in the three groups, as was the frequency of
Mac-1+ monocytes in peripheral blood (Table III). Finally, blood urea nitrogen
levels, GN severity, and intensity of IgG kidney deposits were also
very similar between the T cell-reconstituted and control WT mice
regardless of the gender origin of T cells (Table IV). Overall, the results indicate that
homeostatically proliferating mature T cells of male or female BXSB
origin are equally capable of inducing an early life, lupus disease in
the + T cell-deficient male BXSB
background.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-deleted BXSB mice, that + T cells
are necessary for lupus expression in this strain. The
+ T cell-deficient male mice showed no
mortality after 9 mo and had severely reduced serum IgG and
antichromatin autoantibody levels, decreased peripheral blood
monocytosis, and minor grades of GN. The full spectrum of disease
could, however, be reconstituted in these male T cell-deficient mice by
both Yaa+ (male BXSB) and
Yaa- (female BXSB) T cells, thereby
documenting that homeostatic anti-self T cell proliferation can
induce systemic autoimmunity in an appropriate background, and that the
Yaa gene functions by impacting a non-T cell component.
It is of considerable interest that the absence of
+ T cells led to an almost complete
elimination of disease in the BXSB males. This effect was more
pronounced than that observed by Craft and associates (2)
in similarly TCR-deleted MRL-Faslpr
mice in which only partial protection from disease was afforded. In
this strain concurrent deletion of both the and genes, and thus
of both + and +
T cells, was required for nearly complete elimination of serologic and
histologic disease parameters (3). The present findings in
the BXSB mouse are also at some variance with the initial studies by
Wen et al. (28), who reported that
+ T cell-deficient normal background mice
showed expansion of B cells and secretion of T-dependent isotype
autoantibodies (IgG1 and IgE) with a spectrum of specificities similar
to those in lupus, suggesting that autoantibody induction can be
mediated by + T cells. Adoptive transfer
experiments into SCID mice by these investigators indeed showed that
+ T cells are capable of providing help to
B cells in the absence of + T cells
(20). It appears, therefore, that the ability of
+ T cells to promote systemic autoimmunity
is dependent upon additional genetic and/or environmental factors.
Recent studies have shown that CD4+
+ T cells of
MRL-Faslpr mice are hyper-responsive to
antigenic stimuli (29). Such enhanced responses may also
be applicable to MRL-Faslpr, but not to
BXSB, + T cells.
A unique characteristic of the BXSB male disease, originally identified
by Wofsy et al. (24), is the appearance of a late-onset
monocytosis, almost exclusively detected in the peripheral blood. These
cells appear atypical in that despite expressing Mac-1 and having
morphological features of macrophages, they are devoid of MHC class II
molecules. The origin and potential contribution of these cells to the
disease process remain unclear. The present study as well as a previous
study in which monocytosis was reduced in BXSB male mice treated with
anti-CD4 Ab (10) document that this peculiar
manifestation is highly T cell dependent. The means by which T cells
induce mobilization of these monocyte-like cells remains unknown, but
several products of activated T cells, including IFN-
(30), M-CSF (30), and GM-CSF
(31), might be the mediators. It is apparent, however,
that simple activation of T cells and secretion of
monocytosis-promoting products cannot fully account for this
manifestation, since large numbers of activated T cells are also
present in other lupus strains of mice that do not exhibit this
characteristic. It is possible, therefore, that induction of the
putative T cell-derived factor(s) is directly or indirectly connected
to the presence of the Yaa gene. The picture becomes more
complicated, however, if one considers that this monocytosis does not
occur in a long-lived subline of BXSB male mice previously established
in this laboratory (32). Because appropriate breeding
experiments showed that longevity in this BXSB subline was not due to a
modification of the Yaa gene, it should be concluded that
the monocytosis-promoting factor(s) is an intermediary between T cells
and the Yaa gene product. Further studies on the means of
induction, homing patterns, marker acquisition, and functional
characteristics of these monocyte-like cells are, therefore, highly
warranted.
The mode by which the Yaa gene defect accelerates a lupus-like disease in appropriate backgrounds has not been fully elucidated, and the actual gene remains unknown. Nevertheless, Izui and associates (12, 13, 14) showed that in bone marrow chimeras containing two sets of T and B cells from mice with or without the Yaa gene, the T cells from either Yaa- nonautoimmune mice or Yaa+ autoimmune mice were equally efficient in promoting anti-DNA and anti-gp70 autoantibody production by Yaa+ B cells. Therefore, they concluded that the Yaa gene defect is not functionally expressed in T cells, but only in B cells (and/or other APCs), and suggested that this defect leads to the engagement of otherwise quiescent, low avidity, self-reactive T cells. Indeed, recent studies have shown that normal mice harbor a large cohort of these normally harmless cells, which, under certain circumstances, such as high peptide presentation and costimulation, may acquire effector function and become harmful (33).
Our findings with adoptive transfers of
Yaa+ and Yaa-
BXSB mature T cells into the + T
cell-deficient BXSB male mice are in full congruence with the above
conclusions and further extend the results of Izui and associates
(12, 13, 14) in demonstrating full recapitulation of the
male-like BXSB disease with either type of T cell. Adoptive transfer
experiments with mature T cells became feasible through the
availability of the lymphopenic (i.e.,
TCR-/-) BXSB mice, wherein transferred T
cells survived and homeostatically expanded to reconstitute the normal
lymphocyte pool. Numerous recent studies have documented that
homeostatic T cell proliferation in the periphery is based on
recognition of self-MHC/peptide ligands similar to those used in
intrathymic positive selection, and the expanded cells acquire
activation markers as well as effector function (25, 26, 27).
Of interest, however, only a small fraction (15%) of mature T cells
are expected to engraft and proliferate in a lymphopenic host
(34). Why only a small fraction exhibits this capacity is
unclear, but likely possibilities include the absence or low expression
levels in the periphery of some of the positive selection-mediating
thymic peptides, restriction of proliferative capacity to T cells with
higher anti-self avidity, and/or cell death. Accordingly, skewing
of the V TCR repertoire and a reduction in humoral responses to
diverse Ags following homeostatic expansion of polyclonal T cell
populations have been observed (35). In our transfers of
4–5 x 106 mature T cells, it can therefore
be calculated that reconstitution of the T cell pool occurred via the
expansion of as few as 6–7 x 105 (15%)
T cells. These few cells, likely to encompass a small repertoire of
TCRs, were, nevertheless, sufficient to induce the full serologic and
histologic spectrum of the male BXSB disease. In future studies, we
will determine the minimum number of T cells required to induce disease
via homeostatic expansion in this setting. These issues aside, it can
be hypothesized that anti-self-homeostatic expansion of T cells in
appropriate backgrounds may play a primary or secondary role in the
initiation and perpetuation of systemic autoimmunity, and the findings
presented herein provide initial evidence that this might be the
case.
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Acknowledgments |
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-/- mice, D. Balomenos for
initial mouse breeding, and M. Kat Occhipinti-Bender for editorial
help. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Argyrios N. Theofilopoulos, Department of Immunology-IMM3, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: argyrio{at}scripps.edu
3 Abbreviations used in this paper: Yaa, Y chromosome-associated accelerator; GN, glomerulonephritis; LN, lymph node; WT, wild type.
Received for publication April 6, 2001. Accepted for publication June 4, 2001.
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References |
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