Failure of CD25+ T cells from lupus-prone mice to suppress lupus glomerulonephritis and sialoadenitis

The development of organ-specific autoimmune diseases in mice thymectomized on day 3 of life (d3tx mice) can be prevented by transferring CD4(+)CD25(+) T cells from syngeneic, normal adult mice. Using a d3tx model, we asked whether CD4(+)CD25(+) T cell deficiency contributes to glomerulonephritis (GN) in lupus-prone mice. New Zealand Mixed 2328 (NZM2328) mice spontaneously develop autoantibodies to dsDNA and female-dominant, fatal GN. After d3tx, both male and female NZM2328 mice developed 1) accelerated dsDNA autoantibody response, 2) early onset and severe proliferative GN with massive mesangial immune complexes, and 3) autoimmune disease of the thyroid, lacrimal gland, and salivary gland. The d3tx male mice also developed autoimmune prostatitis. The transfer of CD25(+) cells from 6-wk-old asymptomatic NZM2328 donors effectively suppressed dsDNA autoantibody and the development of autoimmune diseases, with the exception of proliferative lupus GN and sialoadenitis. This finding indicates that NZM2328 lupus mice have a selective deficiency in T cells that regulates the development of lupus GN and sialoadenitis. After d3tx, the proliferative GN of female mice progressed to fatal GN, but largely regressed in the male, thereby revealing a checkpoint in lupus GN progression that depends on gender.     

Paucity of clinical disease despite serological autoimmunity and kidney pathology in lupus-prone New Zealand mixed 2328 mice deficient in BAFF

Constitutive overexpression of B cell-activating factor belonging to the TNF family (BAFF) promotes development of systemic lupus erythematosus (SLE), and treatment of SLE mice with BAFF antagonists ameliorates disease. To determine whether SLE can develop de novo in BAFF-deficient hosts, BAFF-deficient New Zealand Mixed (NZM) 2328 (NZM.Baff(-/-)) mice were generated. In NZM.Baff(-/-) mice, spleen B cells (including CD5(+) B1a and CD5(-) B1b B cells), germinal centers, Ig-secreting cells, and T cells were reduced in comparison to NZM.Baff(+/+) mice. Serum total Ig and autoantibody levels were reduced at 4-6 mo but approached wild-type levels with increasing age, indicating that autoreactive B cells can survive and secrete autoantibodies despite the complete absence of BAFF. At least some of these autoantibodies are nephrophilic in that glomerular deposition of total IgG and IgG1 (but not of IgG2a, IgG2b, or C3) was substantial in NZM.Baff(-/-) mice by 12-13 mo of age. Despite proliferative glomerulonephritis, highlighted by widespread glomerular hyaline thrombi, being common among NZM.Baff(-/-) mice by 6-7 mo of age, severe proteinuria and mortality were greatly attenuated. These results demonstrate that the lifelong absence of BAFF does not protect NZM 2328 mice from serological autoimmunity and renal pathology. Nevertheless, the character of the renal pathology is altered, and the mice are largely spared from clinically overt disease (severe proteinuria and premature death). These observations may have profound ramifications for the use of BAFF antagonists in human SLE and related diseases.     

B Cell and BAFF dependence of IFN-α-exaggerated disease in systemic lupus erythematosus-prone NZM 2328 mice

IFN-α is a potent activator of innate and adaptive immunity, and its administration to preautoimmune (NZB×NZW)F1 mice promotes virulent systemic lupus erythematosus (SLE) disease. Given the known contributions of B cells and BAFF to SLE, we evaluated the ability of IFN-α administration to induce disease in wild-type (WT), B cell-deficient, and BAFF-deficient NZM 2328 mice. Whereas WT mice rapidly developed proliferative glomerulonephritis, marked proteinuria, and increased mortality in response to IFN-α administration, B cell-deficient mice developed neither renal pathology nor clinical disease. Moreover, BAFF-deficient mice, despite developing limited glomerular IgG and C3 deposition, also remained free of histological glomerulonephritis and clinical disease. Strikingly, similar T cell expansion and serum IgG responses were observed in adenovirus (Adv)-IFN-treated WT and BAFF-deficient mice despite their disparate pathological and clinical responses, whereas numbers of activated B cells increased in WT mice but not in BAFF-deficient mice. Nonetheless, B cell, plasma cell, and T cell infiltration of the kidneys in Adv-IFN-treated WT mice was similar to that in WT mice treated with Adv-control. Its ability to promote SLE disease in WT mice notwithstanding, IFN-α administration failed to drive the preferential expansion of CD4(+) memory T cells that occurs during the natural course of disease, and glomerular infiltration of macrophages failed to associate with development of disease. These results collectively suggest that therapeutic targeting in SLE of BAFF and/or B cells in SLE could be successful even in states of IFN-α overexpression. Moreover, our results document important biological differences between IFN-α-driven and spontaneous natural SLE disease.     

HMGB1 protein promotes glomerular mesangial matrix deposition via TLR2 in lupus nephritis

Lupus nephritis (LN) is the most common complication of systemic lupus erythematosus. Patients with LN mostly die of sclerosing glomerulonephritis and renal failure. The inhibition of glomerular mesangial matrix deposition is an efficient method to restrict the progress of renal injury. By recognizing and binding extracellular and intracellular ligands, Toll-like receptor 2 (TLR2) contributes to the pathogenesis of most immune diseases. However, the relationship between TLR2 and LN is still unknown. Our previous studies confirmed that high-mobility group box 1 (HMGB1), an important ligand of TLR2, promotes the progression of LN by inducing the proliferation of glomerular mesangial cells. However, whether or not HMGB1 participates in the pathogenesis of glomerular mesangial matrix deposition in LN remains unknown. In this study, we observed the upregulated expression of TLR2 in the glomeruli of LN patients and MRL/lpr mice. The inhibition of either TLR2 or HMGB1 inhibited the release of fibronectin and the activation of the MyD88/NF-κB pathway in mesangial cells cultured with LN plasma. In addition, both TLR2- and HMGB1-deficient mice showed reduced 24 hr urine protein levels and improved glomerular histological changes and sclerosis levels. These results indicate that TLR2 regulates glomerular mesangial matrix deposition in LN through the activation of the MyD88/NF-κB pathway by binding to HMGB1.     

Severe focal sialadenitis and dacryoadenitis in NZM2328 mice induced by MCMV: a novel model for human Sjögren's syndrome

The genetic and environmental factors that control the development of Sj?gren's syndrome, an autoimmune disease mainly involving the salivary and lacrimal glands, are poorly understood. Viruses which infect the glands may act as a trigger for disease. The ability of sialotropic murine CMV (MCMV) to induce acute and chronic glandular disease was characterized in an autoimmune-prone mouse strain, NZM2328. MCMV levels were detectable in the salivary and lacrimal glands 14-28 days after i.p. infection and correlated with acute inflammation in the submandibular gland. After latency, virus was undetectable in the glands by PCR. At this stage, NZM2328 female mice developed severe chronic periductal inflammation in both submandibular and lacrimal glands in contrast to the much milder infiltrates found in female B6-lpr and male NZM2328. The focal infiltrates consisted of CD4+ and B220+ cells as opposed to diffuse CD4+, CD8+, and B220+ cells during acute infection. Salivary gland functional studies revealed a gender-specific progressive loss of secretory function between days 90 and 125 postinfection. Latent MCMV infection did not significantly affect the low incidence of autoantibodies to Ro/SSA and La/SSB Ags in NZM2328 mice. However, reactivities to other salivary and lacrimal gland proteins were readily detected. MCMV infection did not significantly alter the spontaneous onset of kidney disease in NZM2328. Thus, chronic inflammation induced by MCMV with decreased secretory function in NZM2328 mice resembles the disease manifestations of human Sj?gren's syndrome.     

Susceptibility to T cell-mediated injury in immune complex disease is linked to local activation of renin-angiotensin system: the role of NF-AT pathway

FcR provides a critical link between ligands and effector cells in immune complex diseases. Emerging evidence reveals that angiotensin (Ang)II exerts a wide variety of cellular effects and contributes to the pathogenesis of inflammatory diseases. In anti-glomerular basement membrane Ab-induced glomerulonephritis (GN), we have previously noted that FcR-deficient mice (gamma(-/-)) surviving from lethal initial damage still developed mesangial proliferative GN, which was drastically prevented by an AngII type 1 receptor (AT1) blocker. We further examined the mechanisms by which renin-Ang system (RAS) participates in this immune disease. Using bone marrow chimeras between gamma(-/-) and AT1(-/-) mice, we found that glomerular injury in gamma(-/-) mice was associated with CD4(+) T cell infiltration depending on renal AT1-stimulation. Based on findings in cutaneous delayed-type hypersensitivity, we showed that AngII-activated renal resident cells are responsible for the recruitment of effector T cells. We next examined the chemotactic activity of AngII-stimulated mesangial cells, as potential mechanisms coupling RAS and cellular immunity. Chemotactic activity for T cells and Th1-associated chemokine (IFN-gamma-inducible protein-10 and macrophage-inflammatory protein 1alpha) expression was markedly reduced in mesangial cells from AT1(-/-) mice. Moreover, this activity was mainly through calcineurin-dependent NF-AT. Although IFN-gamma-inducible protein-10 was NF-kappaB-dependent, macrophage-inflammatory protein 1alpha was dominantly regulated by NF-AT. Furthermore, AT1-dependent NF-AT activation was observed in injured glomeruli by Southwestern histochemistry. In conclusion, our data indicate that local RAS activation, partly via the local NF-AT pathway, enhances the susceptibility to T cell-mediated injury in anti-glomerular basement membrane Ab-induced GN. This novel mechanism affords a rationale for the use of drugs interfering with RAS in immune renal diseases.     

Trypanosoma cruzi: maintenance of parasite-specific T cell responses in lymph nodes during the acute phase of the infection

Mice infected with 5 x 10(3) forms of Trypanosoma cruzi showed a transient, but severe impairment of in vitro spleen cell responses to parasite antigens and to Concanavalin A (Con A). In contrast, inguinal and periaortic lymph node (LN) cells displayed high parasite-specific proliferative responses and only a partial reduction of the Con A-induced proliferation during the acute and chronic phases of infection. Lymphocytes that underwent blastic transformation in T. cruzi-stimulated cell cultures were of the L3T4+ phenotype. Suppression of spleen cell responses occurred in the acute phase whether mice were infected with high (3 x 10(5] or low (5 x 10(3] doses of T. cruzi by intraperitoneal or subcutaneous route. Suppression of the T. cruzi-specific proliferative response of LN cells was only observed in mice infected with high subcutaneous inocula. This suppression, however, was restricted to the LNs draining the site of inoculation without affecting distant LNs. Supernatants from parasite-stimulated proliferating LN cells displayed low or undetectable T cell growth factor (TCGF) activity, in contrast with the high TCGF levels found in supernatants of the same cells stimulated with Con A. Low levels of TCGF were also detected in cultures of LN cells from mice immunized with T. cruzi extracts. Neither the T. cruzi antigen used for in vitro stimulation nor the LN cell supernatants from infected mice inhibited TCGF activity. These findings indicate that (1) parasite-specific responses are present in the LN compartment throughout the acute phase of T. cruzi infection in mice and (2) the proliferative response of L3T4+ LN cells from infected mice to T. cruzi antigens is not associated with a high TCGF secretory response.     

Blockade of TGF-beta signaling in T cells prevents the development of experimental glomerulonephritis

Anti-glomerular basement membrane (GBM) Ab-induced glomerulonephritis (GN) at late stage is thought to be mediated by T cells. However, signaling pathways of T cells that are involved in the development of anti-GBM Ab-induced GN are unclear. We have recently established transgenic mice expressing Smad7, an inhibitor of TGF-beta signaling, in mature T cells, where signaling by TGF-beta was blocked specifically in T cells. In this study, we showed that anti-GBM Ab-induced GN was suppressed in several measures in the transgenic mice including the severity of glomerular changes, proteinuria, renal function, and CD4 T cell infiltration into the glomeruli without down-regulation of CD62 ligand (CD62L) (L-selectin) expression on CD4 T cells. Furthermore, treatment with the soluble fusion protein of CD62L and IgG enhanced anti-GBM Ab-induced GN. These findings indicated that blockade of TGF-beta signaling in T cells prevented the development of anti-GBM Ab-induced GN. Because CD62L on T cells appears to be inhibitory for the development of anti-GBM Ab-induced GN, persistent expression of CD62L on CD4 T cells may explain, at least in part, the suppression of anti-GBM Ab-induced GN in the transgenic mice. Our findings suggest that the development of anti-GBM Ab-induced GN requires TGF-beta/Smad signaling in T cells.     

Genetic dissection of Sle pathogenesis: Sle3 on murine chromosome 7 impacts T cell activation, differentiation, and cell death.

Polyclonal, generalized T cell defects, as well as Ag-specific Th clones, are likely to contribute to pathology in murine lupus, but the genetic bases for these mechanisms remain unknown. Mapping studies indicate that loci on chromosomes 1 (Sle1), 4 (Sle2), 7 (Sle3), and 17 (Sle4) confer disease susceptibility in the NZM2410 lupus strain. B6.NZMc7 mice are C57BL/6 (B6) mice congenic for the NZM2410-derived chromosome 7 susceptibility interval, bearing Sle3. Compared with B6 controls, B6.NZMc7 mice exhibit elevated CD4:CD8 ratios (2.0 vs 1.34 in 1- to 3-mo-old spleens); an age-dependent accumulation of activated CD4+ T cells (33.4% vs 21.9% in 9- to 12-mo-old spleens); a more diffuse splenic architecture; and a stronger immune response to T-dependent, but not T-independent, Ags. In vitro, Sle3-bearing T cells show stronger proliferation, increased expansion of CD4+ T cells, and reduced apoptosis (with or without anti-Fas) following stimulation with anti-CD3. With age, the B cells in this strain acquire an activated phenotype. Thus, the NZM2410 allele of Sle3 appears to impact generalized T cell activation, and this may be causally related to the low grade, polyclonal serum autoantibodies seen in this strain. Epistatic interactions with other loci may be required to transform this relatively benign phenotype into overt autoimmunity, as seen in the NZM2410 strain.     

Crescentic glomerulonephritis--a manifestation of a nephritogenic Th1 response?

Crescentic glomerulonephritis (GN) is the histopathological correlate of the clinical syndrome of rapidly progressive glomerulonephritis. Glomerular crescent formation complicates proliferative forms of GN and indicates severe disease with a poor renal prognosis. In the past 10 years evidence from experimental models of GN and from human disease has accumulated suggesting that crescentic glomerulonephritis is a manifestation of a delayed type hypersensitivity (DTH)-like response to nephritogenic antigens. The elucidation of T helper 1 (Th1) and Th2 subsets in mice and in humans has led to the hypothesis that crescentic GN is a manifestation of a Th1 predominant DTH mediated immune response. Recent experiments performed mainly in a murine model of crescentic glomerulonephritis have tested this hypothesis. Crescent formation in this model is substantially interleukin (IL)-12 and interferon-gamma (IFN-gamma) dependent. Administration of IL-12, deletion of endogenous IL-4 or IL-10 results in enhanced disease, while administration of exogenous IL-4 and/or IL-10 reduces crescentic injury. These findings, together with the available evidence from human studies (examining the pattern of immune effectors in glomeruli, data on cytokine production by peripheral blood mononuclear cells and case reports of the induction of proliferative and/or crescentic GN by administration of IFN-gamma or IL-2) suggest that human crescentic GN is manifestation of a Th1 mediated DTH-like nephritogenic immune response.     

Apolipoprotein A-I Modulates Regulatory T Cells in Autoimmune LDLr?/?, ApoA-I?/? Mice

The immune system is complex, with multiple layers of regulation that serve to prevent the production of self-antigens. One layer of regulation involves regulatory T cells (Tregs) that play an essential role in maintaining peripheral self-tolerance. Patients with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis have decreased levels of HDL, suggesting that apoA-I concentrations may be important in preventing autoimmunity and the loss of self-tolerance. In published studies, hypercholesterolemic mice lacking HDL apoA-I or LDLr^−/−, apoA-I^−/− (DKO), exhibit characteristics of autoimmunity in response to an atherogenic diet. This phenotype is characterized by enlarged cholesterol-enriched lymph nodes (LNs), as well as increased T cell activation, proliferation, and the production of autoantibodies in plasma. In this study, we investigated whether treatment of mice with lipid-free apoA-I could attenuate the autoimmune phenotype. To do this, DKO mice were first fed an atherogenic diet containing 0.1% cholesterol, 10% fat for 6 weeks, after which treatment with apoA-I was begun. Subcutaneous injections of 500 μg of lipid-free apoA-I was administered every 48 h during the treatment phase. These and control mice were maintained for an additional 6 weeks on the diet. At the end of the 12-week study, DKO mice showed decreased numbers of LN immune cells, whereas Tregs were proportionately increased. Accompanying this increase in Tregs was a decrease in the percentage of effector/effector memory T cells. Furthermore, lipid accumulation in LN and skin was reduced. These results suggest that treatment with apoA-I reduces inflammation in DKO mice by augmenting the effectiveness of the LN Treg response.     

IFN-gamma production by intrinsic renal cells and bone marrow-derived cells is required for full expression of crescentic glomerulonephritis in mice

The contribution of IFN-gamma from bone marrow (BM) and non-BM-derived cells to glomerular and cutaneous delayed-type hypersensitivity (DTH) was studied in mice. Chimeric IFN-gamma mice (IFN-gamma(+/+) BM chimera), in which IFN-gamma production was restricted to BM-derived cells, were created by transplanting normal C57BL/6 (wild-type (WT)) BM into irradiated IFN-gamma-deficient mice. BM IFN-gamma-deficient chimeric mice (IFN-gamma(-/-) BM chimera) were created by transplanting WT mice with IFN-gamma-deficient BM. WT and sham chimeric mice (WT mice transplanted with WT BM) developed crescentic glomerulonephritis (GN) with features of DTH (including glomerular T cell and macrophage infiltration) in response to an Ag planted in their glomeruli and skin DTH following subdermal Ag challenge. IFN-gamma-deficient mice showed significant protection from crescentic GN and reduced cutaneous DTH. IFN-gamma(+/+) BM chimeric and IFN-gamma(-/-) BM chimeric mice showed similar attenuation of crescentic GN as IFN-gamma-deficient mice, whereas cutaneous DTH was reduced only in IFN-gamma(-/-) BM chimeras. In crescentic GN, IFN-gamma was expressed by tubular cells and occasional glomerular cells and was colocalized with infiltrating CD8(+) T cells, but not with CD4(+) T cells or macrophages. Renal MHC class II expression was reduced in IFN-gamma(+/+) BM chimeric mice and was more severely reduced in IFN-gamma-deficient mice and IFN-gamma(-/-) BM chimeric mice. These studies show that IFN-gamma expression by both BM-derived cells and intrinsic renal cells is required for the development of crescentic GN, but IFN-gamma production by resident cells is not essential for the development of cutaneous DTH.     

Localization in situ of type VI collagen protein and its mRNA in mesangial proliferative glomerulonephritis using renal biopsy sections

 Extracellular matrix accumulation is crucial in the pathogenesis of glomerulosclerosis in mesangial proliferative glomerulonephritis (GN). In an attempt to explore the distribution of type VI collagen and its synthesizing cells in normal and diseased glomeruli, we investigated mRNA and protein expression of type VI collagen in renal biopsy sections, histologically diagnosed as mesangial proliferative GN. Five renal biopsies from patients diagnosed as having minor glomerular abnormalities and one surgical renal tissue were also simultaneously examined as controls. Immunohistochemical studies revealed type VI collagen immunostaining in the mesangium and glomerular basement membrane of the control glomeruli. Compared to the control, increased deposition of type VI collagen was noted in the mesangial proliferative and sclerotic lesions in GN. To identify the cells responsible for the synthesis of type VI collagen mRNA, renal sections were hybridized in situ with digoxigenin-labeled antisense oligo-DNA probe complementary to a part of α1 (VI) mRNA. Occasionally intraglomerular cells hybridized with digoxigenin-labeled antisense pro α1 (VI) oligo-DNA in control glomeruli. An increased number of intraglomerular cells (mostly epithelial cells) were, however, positive for α1 (VI) mRNA expression in GN sections. The present study documents the distribution of type VI collagen in the normal glomeruli and provides further evidence of accelerated synthesis of this collagen in mesangial proliferative GN. Accepted: 21 July 1998     

T cell priming in vivo: a major role for B cells in presenting antigen to T cells in lymph nodes

Previous studies have shown that lymph node (LN) T cells from mice given repeated injections of anti-mu antisera from birth (mu sm) fail to mount secondary T proliferative responses to antigen in vitro after s.c. priming in vivo. This finding raised the possibility that priming of T cells in LN depends on the presence of B cells, Ig+ B lymphocytes being absent in mu sm. In support of this idea, the present paper shows that the priming defect in LN of mu sm can be largely overcome by injecting B cell populations s.c. 1 day before s.c. priming with antigen. Restoration of LN priming was observed with s.c. injection of highly purified populations of small B cells but not with heat-killed or lightly irradiated B cells. Homing studies indicated that approximately 10% of s.c.-injected B cells reached the draining LN. In other studies, irradiated mice injected i.v. with purified T cells manifested poor priming in LN after s.c. injection of antigen. It was reasoned that the LN priming defect in this situation reflected the lack of B cells in irradiated mice, B cells being highly radiosensitive. In support of this notion, it was found that s.c. injection of B cells into irradiated recipients of T cells led to high priming of T cells in LN after s.c. injection of antigen. Although T cells exposed to antigen in B-depleted LN of mu sm and irradiated mice gave negligible T proliferative responses in vitro, low but significant levels of primed T helper function were detected in a sensitive T helper assay in vivo. In light of this finding, our working hypothesis is that the initial induction of T cells to antigen in LN is controlled by resident dendritic cells (or other non-B antigen-presenting cells), the main role of B cells being to control the clonal expansion of activated T cells.     

In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis

The most prevalent severe manifestation of systemic lupus erythematosus is nephritis, which is characterized by immune complex deposition, inflammation, and scarring in glomeruli and the tubulointerstitium. Numerous studies indicated that glomerulonephritis results from a systemic break in B cell tolerance, resulting in the local deposition of immune complexes containing Abs reactive with ubiquitous self-Ags. However, the pathogenesis of systemic lupus erythematosus tubulointerstitial disease is not known. In this article, we demonstrate that in more than half of a cohort of 68 lupus nephritis biopsies, the tubulointerstitial infiltrate was organized into well-circumscribed T:B cell aggregates or germinal centers (GCs) containing follicular dendritic cells. Sampling of the in situ-expressed Ig repertoire revealed that both histological patterns were associated with intrarenal B cell clonal expansion and ongoing somatic hypermutation. However, in the GC histology, the proliferating cells were CD138(-)CD20(+) centroblasts, whereas they were CD138(+)CD20(low/-) plasmablasts in T:B aggregates. The presence of GCs or T:B aggregates was strongly associated with tubular basement membrane immune complexes. These data implicate tertiary lymphoid neogenesis in the pathogenesis of lupus tubulointerstitial inflammation.     

Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis

Costimulatory blockade with CTLA4Ig and anti-CD40L along with a single dose of cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F(1) mice. To understand the mechanisms for remission and for impending relapse, we examined the expression profiles of 61 inflammatory molecules in the perfused kidneys of treated mice and untreated mice at different stages of disease. Further studies using flow cytometry and immunohistochemistry allowed us to determine the cellular origins of several key markers. We show that only a limited set of inflammatory mediators is expressed in the kidney following glomerular immune complex deposition but before the onset of proteinuria. Formation of a lymphoid aggregate in the renal pelvis precedes the invasion of the kidney by inflammatory cells. Regulatory molecules are expressed early in the disease process and during remission but do not prevent the inevitable progression of active inflammation. Onset of proliferative glomerulonephritis and proteinuria is associated with activation of the renal endothelium, expression of chemokines that mediate glomerular cell infiltration, and infiltration by activated dendritic cells and macrophages that migrate to different topographical areas of the kidney but express a similar profile of inflammatory cytokines. Increasing interstitial infiltration by macrophages and progressive tubular damage, manifested by production of lipocalin-2, occur later in the disease process. Studies of treated mice identify a type II (M2b)-activated macrophage as a marker of remission induction and impending relapse and suggest that therapy for systemic lupus erythematosus nephritis should include strategies that prevent both activation of monocytes and their migration to the kidney.     

Regulatory T cells in systemic lupus erythematosus: past,present and future

Regulatory/suppressor T cells (Tregs) maintain immunologic homeo-stasis and prevent autoimmunity. In this article, past studies and recent studies of Tregs in mouse models for lupus and of human systemic lupus erythematosus are reviewed concentrating on CD4⁺CD25⁺Foxp3⁺ Tregs. These cells consist of thymus-derived, natural Tregs and peripherally induced Tregs that are similar phenotypically and functionally. These Tregs are decreased in young lupus-prone mice, but are present in normal numbers in mice with established disease. In humans, most workers report CD4⁺Tregs are decreased in subjects with active systemic lupus erythematosus, but the cells increase with treatment and clinical improvement. The role of immunogenic and tolerogenic dendritic cells in controlling Tregs is discussed, along with new strategies to normalize Treg function in systemic lupus erythematosus.     

Regulation of T cell priming by lymphoid stroma

The priming of immune T cells by their interaction with dendritic cells (DCs) in lymph nodes (LN), one of the early events in productive adaptive immune responses, occurs on a scaffold of lymphoid stromal cells, which have largely been seen as support cells or sources of chemokines and homeostatic growth factors. Here we show that murine fibroblastic reticular cells (FRCs), isolated from LN of B6 mice, play a more direct role in the immune response by sensing and modulating T cell activation through their upregulation of inducible nitric oxide synthase (iNOS) in response to early T cell IFNγ production. Stromal iNOS, which only functions in very close proximity, attenuates responses to inflammatory DC immunization but not to other priming regimens and preferentially affects Th1 cells rather than Th2. The resultant nitric oxide production does not affect T cell-DC coupling or initial calcium signaling, but restricts homotypic T cell clustering, cell cycle progression, and proliferation. Stromal feedback inhibition thus provides basal attenuation of T cell responses, particularly those characterized by strong local inflammatory cues.     

Sequential appearance of host-derived T cell subsets during differentiation in nude mice grafted with rat fetal thymus

To elucidate the abnormality of T cell differentiation in nude mice grafted with rat fetal thymus that develop multiple-organ-localized autoimmune diseases, we examined sequential appearance of T cell subsets and expression of TCR genes in BALB/c nude mice after grafting with fetal F344 rat thymus. We observed progressive expression of TCR gamma/delta-alpha/beta genes in the lymph node (LN) cells from 8 to 12 wk after grafting. An appreciable number of CD4+ T cells but few CD8+ T cells were detected in the LN at 8 wk after grafting. CD8+ T cells increased slowly in number by 12 wk after grafting but remained at a low level in comparison with those in nude mice 12 wk after grafting with BALB/c thymus. In correlation with an increase in the number of T cells expressing TCR alpha/beta genes, alloreactivity as assessed by MLR was increased to a normal level. However, CTL activity against alloantigens remained at a low level in the LN cells at 12 wk. At this stage, organ-specific autoimmune diseases and a high level of anti-DNA autoantibodies were detected. In these mice host-reactive T cells such as V beta 3- or V beta 11-bearing T cells were virtually eliminated in the peripheral mature T cell pool, whereas T cells maturing in the fetal rat thymus significantly proliferated in response to donor-rat stimulator cells. These results suggest that the development of the autoimmune diseases may be ascribed to an impaired maturation of CD8+ T cells but not to failure in clonal elimination of host-reactive T cells in nude mice grafted with rat thymus.