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Class I_B-Phosphatidylinositol 3-Kinase (PI3K) Deficiency Ameliorates I_A-PI3K-Induced Systemic Lupus but Not T Cell Invasion¹

Domingo F. Barber^*, Almira Bartolomé^*, Carmen Hernandez^*, Juana M. Flores, Cristina Fernandez-Arias^*, Luis Rodríguez-Borlado^*, Emilio Hirsch, Matthias Wymann, Dimitrios Balomenos^* and Ana C. Carrera^2,*

^* Department of Immunology and Oncology, and Animal Facility, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain; Department of Animal Medicine and Surgery, Veterinary School, Universidad Complutense de Madrid, Madrid, Spain; Department of Genetics Biology and Biochemistry, University of Torino, Turin, Italy; and Institute of Biochemistry, University of Fribourg, Fribourg, Switzerland

	Abstract

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Class I PI3K catalyzes formation of 3-poly-phosphoinositides. The family is divided into I_A isoforms, activated by Tyr kinases and the I_B isoform (PI3K), activated by G protein-coupled receptors. Mutations that affect PI3K are implicated in chronic inflammation, although the differential contribution of each isoform to pathology has not been elucidated. Enhanced activation of class I_A-PI3K in T cells extends CD4⁺ memory cell survival, triggering an invasive lymphoproliferative disorder and systemic lupus. As both I_A- and I_B-PI3K isoforms regulate T cell activation, and activated pathogenic CD4⁺ memory cells are involved in triggering systemic lupus, we examined whether deletion of I_B could reduce the pathological consequences of increased I_A-PI3K activity. I_B-PI3K deficiency did not abolish invasion or lymphoproliferation, but reduced CD4⁺ memory cell survival, autoantibody production, glomerulonephritis, and systemic lupus. Deletion of the I_B-PI3K isoform thus decreased survival of pathogenic CD4⁺ memory cells, selectively inhibiting systemic lupus development. These results validate the PI3K isoform as a target for systemic lupus erythematosus treatment.

	Introduction

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The PI3K are dual-specific lipid and protein kinases that participate in numerous cellular responses. The class I-PI3K are subdivided into class I_A and I_B. Class I_A-PI3K consists of three catalytic subunits, p110, p110, or p110, which form complexes with the p85 regulatory subunits, and are activated by tyrosine kinase receptor signaling. Class I_B is composed of the catalytic subunit p110, and is activated mainly by G protein-coupled receptors (GPCR)³ (1, 2). Mutations in the PI3K pathway are involved in tumor generation, as well as in chronic inflammatory lupus-like disease (3, 4, 5). Although PI3K is a promising therapeutic target, knowledge of isoform-specific functions remains limited.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease, characterized at early stages by an increase in autoreactive/memory CD4⁺ cells (6, 7, 8, 9, 10, 11, 12). Deregulated T cells help trigger polyclonal B cell activation, giving rise to generalized B cell expansion, hypergammaglobulinemia, and increased autoantibody production. Circulating anti-DNA Ab form complexes that are captured in kidney, activating the complement cascade. As disease progresses, T cells and macrophages infiltrate the kidney and amplify the local inflammatory response (8). At advanced stages, mesangial proliferation, vascular collapse, and immune complex accumulation in kidney result in glomerulonephritis (GN) and renal failure (6, 7, 8, 9).

Deregulation of T cell homeostasis is a critical early event in SLE (10, 11, 12). Both I_A- and I_B-PI3K regulate T cell differentiation, activation, and survival. I_B-PI3K-deficient mice show T cell differentiation defects and reduced mature T cell activation (13, 14, 15). Deletion of the I_A isoform PI3K reduces T cell activation (16); the I_A isoforms PI3K and may also affect T cell activation, although this remains untested because deficiency in these isoforms is lethal in embryos (17, 18). Enhanced activation of I_A isoforms by p65^PI3K transgene expression in T cells increases CD4⁺ cell differentiation (15). In mature T cells, p65^PI3K transgene expression enhances survival, triggering an invasive lymphoproliferative disease and systemic lupus (3). Deletion of the negative regulator of the class I PI3K pathway, the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10, also induces SLE-like disease, confirming the capacity of PI3K to trigger this pathology (5).

We previously showed that enhanced activation of I_A-PI3K compensates some T cell differentiation defects in PI3K^–/– mice (15). Using p65^PI3K transgenic (Tg) mice, we tested whether I_B-PI3K deletion could reduce the invasion, lymphoproliferation, and systemic lupus development induced by increased I_A-PI3K activity in T cells. PI3K deletion did not abolish lymphoproliferation or invasion, but diminished CD4⁺ memory cell survival, leading to amelioration of lupus and prolongation of mouse life span. As an increase in pathogenic CD4⁺ memory cells is a hallmark of multigenic murine and human lupus (6, 7, 8, 9, 10, 11, 12), selective inhibition of memory cell survival by deletion of one PI3K isoform (I_B-PI3K) suggests a treatment for this disease. These observations contribute to understanding the specific functions of I_A- and I_B-PI3K isoforms and their contribution to inflammation.

	Materials and Methods

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Mice

p65^PI3KTg (C57/BL6) and PI3K-deficient (129sv) mice were described previously (3, 13). p65^PI3KTg mice were crossed with PI3K-deficient mice. The F₂ generation was produced by F₁ x F₁ mating: F₃ progeny were used for experiments. Lupus-like disease in p65^PI3KTg PI3K^+/– mice was indistinguishable from that of p65^PI3KTg mice (3). As controls, we used littermates that did not express the transgene and were PI3K^+/– or PI3K^+/+, which presented no obvious differences. Offspring were analyzed by PCR. Mice were bred and maintained under specific pathogen-free conditions at the Centro Nacional de Biotecnología animal facility. The Consejo Superior de Investigaciones Cientificas ethics committee approved the protocols used for experiments with mice.

Flow cytometry and cell death analysis

Spleen and lymph node cell suspensions were prepared; erythrocytes were lysed, and cells were counted. For surface staining, Abs were FITC, PE, or biotin conjugated, and cells were stained with saturating concentrations (4°C). Biotinylated Abs were developed with streptavidin-Spectral Red (Southern Biotechnology Associates). Abs used were CD3 (145-2C11), CD4 (L3T4, H129.19), CD8 (Ly-2, 53-6,7), CD44 (pgp1, IM7), and CD62L (all from BD Pharmingen). The Annexin V^FITC kit was from Corixa. Cells were analyzed on an EPICS XL with System II software (Beckman Coulter). Statistics analyses were performed using the StatView 512⁺ program and the ² test (www.physics.csbju.edu).

Biochemical and serological analyses and histology

Serum Ig and isotype-specific anti-dsDNA Ab were measured, as described (3). Urine protein levels were assessed with Medi-test Protein 2 Strips (Macherey-Nagel) every 15 days. Mice were examined daily; when severe SLE symptoms appeared, affected mice were killed and organs were collected for histology or flow cytometry analysis. Tissues were fixed in 4% Formalin in PBS until processing, as described (3).

	Results

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Prolonged life span in p65^PI3KTg/PI3K-deficient mice

We previously showed that the increase in I_A-PI3K activity induced by p65^PI3K transgene expression in T cells causes accumulation of CD4⁺ memory cells, an invasive lymphoproliferative disorder, and development of SLE-like disease; p65^PI3KTg mice die of renal failure (3). I_A- and I_B-PI3K isoforms exhibit a partial functional compensation during thymic development (15). We thus examined whether I_B-PI3K deletion could reduce the disease generated by enhanced I_A-PI3K activity in mature T cells. p65^PI3KTg mice were crossed with PI3K-deficient mice, and resulting progeny were examined. Mice were euthanized when they showed signs of disease (descamation and proteinuria; data not shown). Histological examination showed that 80% of p65^PI3KTg/PI3K^+/– mice developed renal disease symptoms by 16 mo of age. In contrast, 70% of p65^PI3KTg/PI3K^–/– mice showed no symptoms at this age and 30% remained healthy at 20 mo, near the end of their natural life span (Fig. 1A; Table I). Compared with p65^PI3KTg/PI3K^+/– littermates, p65^PI3KTg/PI3K^–/– mice showed a significantly prolonged life span.

View larger version (38K): [in this window] [in a new window]   FIGURE 1. Prolonged life span and moderate reduction in lymphoproliferation in p65PI3KTg/PI3K–/– mice. A, Percentage of survival of p65PI3KTg/PI3K+/– and p65PI3KTg/PI3K–/– (knockout) littermates. 2 test, p = 0.01. B, Absolute number of splenocytes in p65PI3KTg/PI3K+/–, p65PI3KTg/PI3K knockout, and littermate control mice. Each dot represents a single mouse. C, Absolute number and percentage of CD4+, CD8+, B220+, and CD11b+ cells in splenocyte suspensions from control, p65PI3KTg/PI3K+/–, and p65PI3KTg/PI3K–/– mice. D, H&E staining of lung sections from p65PI3KTg/PI3K+/+ and p65PI3KTg/PI3K–/– mice. Lymphocyte infiltrate (arrows) is seen in both sections. E, Cytofluorometry analysis of lung suspensions from p65PI3KTg/PI3K+/– and p65PI3KTg/PI3K–/– mice. Student’s t test p values are indicated.

View this table: [in this window] [in a new window]   Table I. SLE-like disease in p65PI3KTg/PI3K+/– and p65PI3KTg/PI3K–/– mice

Reduced renal disease in p65^PI3KTg/PI3K-deficient mice

SLE-like disease development is accompanied by polyclonal hypergammaglobulinemia and proteinuria (3, 7). p65^PI3KTg/PI3K^+/– mice developed proteinuria with age, which was low or absent in p65^PI3KTg/PI3K^–/– littermates (data not shown). Total anti-DNA Ab levels, as well as IgM, IgG1, IgG2a, and IgG2b levels, were reduced in p65^PI3KTg/PI3K^–/– mouse serum compared with p65^PI3KTg/PI3K^+/– littermates (Fig. 2A).

View larger version (59K): [in this window] [in a new window]   FIGURE 2. Reduced renal disease in p65PI3KTg/PI3K–/– mice. A, Anti-dsDNA total Ab, IgM, IgG1, IgG2a, and IgG2b in p65PI3KTg/PI3K+/– and p65PI3KTg/PI3K–/– mouse sera. Ab titers are represented as absorbance at OD492 nm at a 1/1600 serum dilution. , Titer of a serum pool from littermate wild-type mice; , mean Ab titer from groups of p65PI3KTg and MRL/lpr mice, which yielded similar results. Student’s t test p values are indicated. B, H&E-stained kidney sections from representative PI3K+/– (normal) and p65PI3KTg/PI3K+/– mice (GN score 3), and two p65PI3KTg/PI3K–/– mice (GN score 1). C, FITC anti-IgG Ab-stained IgG deposits in representative mice. IgG deposits are seen in p65PI3KTg/PI3K+/– mice and are notably reduced or absent in p65PI3KTg/PI3K–/– kidney. Control non-Tg kidney is shown for comparison.

Reduction in CD4⁺ memory T cell numbers in p65^PI3KTg/PI3K-deficient mice

CD4⁺ memory cell accumulation, a characteristic of systemic lupus, is found in p65^PI3KTg mice (3). These cells are implicated in disease development (6, 10, 11, 12). As PI3K regulates T cell activation (14, 15), we examined whether PI3K deletion could reduce CD4⁺ memory cell numbers. Despite the fact that PI3K deletion did not significantly affect the memory T cell pool in non-Tg mice (Fig. 3A), both the proportion and absolute numbers of CD4⁺CD44^high and CD4⁺CD62L^low memory cells were significantly reduced in p65^PI3KTg/PI3K^–/– compared with p65^PI3KTg/PI3K^+/– mice (Fig. 3, A and B). As p65^PI3K-induced CD4⁺ memory T cell expansion involves reduction of cell death rates within this population (3), we examined whether PI3K deletion restores normal CD4⁺ memory T cell death rates in p65^PI3KTg mice. CD4⁺CD44^high memory cell death in vivo was higher in p65^PI3KTg/PI3K^–/– compared with p65^PI3KTg/PI3K^+/– mice (Fig. 3C). Accordingly, spontaneous death of cultured CD4⁺ T cells from p65^PI3KTg/PI3K^–/– mice was also significantly higher than those of p65^PI3KTg/PI3K^+/– mice (Fig. 3D). In addition, we observed reduction of CD4⁺ T cell survival after PI3K deletion in non-Tg mice (Fig. 3D). Together, the findings show that amelioration of lupus disease in p65^PI3KTg/PI3K^–/– mice correlates with reduced CD4⁺ memory cell survival.

View larger version (32K): [in this window] [in a new window]   FIGURE 3. Reduction in CD4+ memory cell numbers in p65PI3KTg/PI3K–/– mice. A, The proportion and absolute numbers of CD4+CD44high and CD4+CD62Llow cells were examined in PI3K+/–, PI3K–/–, p65PI3KTg/PI3K+/–, and p65PI3KTg/PI3K–/– littermate mice spleens. Student’s t test p values are indicated. B, CD44 and CD62L expression was examined in representative control (green), p65PI3KTg/PI3K+/– (red), and p65PI3KTg/PI3K–/– (black) spleens. Percentages of CD44high and CD62Llow cells are indicated. C, CD4+ cell death rates in spleen as examined by log fluorescence intensity of annexin V binding in CD4+CD44high and CD4+CD62Llow populations in control (green), p65PI3KTg/PI3K+/– (red), and p65PI3KTg/PI3K–/– (black) mice. The percentage of annexin V-positive cells is indicated. A representative mouse from one experiment of four with similar results. D, Proportions of viable CD4+ and CD8+ T cells at different time points of in vitro culture, considering initial CD4+ and CD8+ numbers as 100%. PI3K+/– (green), PI3K–/– (dashed black), p65PI3KTg/PI3K+/– (red), and p65PI3KTg/PI3K–/– (black). Comparison of surviving T cells from the different mutant mice with control PI3K+/– mice at day 8 in three assays yielded a significant difference (p < 0.05).

	Discussion

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Normal quiescent T cells have low levels of PI3K lipid products, which increase only after cell activation (1, 2). PI3K-deficient mice show reduced T cell activation and impaired macrophage and neutrophil mobilization; however, they have a relatively normal hemopoietic cell composition in basal conditions (13, 14). Interference with PI3K is thus predicted to induce minor side effects. Enhanced I_A-PI3K activation causes lupus (3, 4, 5). Moreover, endogenous PI3K activation was observed in a graft-vs-host-induced murine systemic lupus model (20) and in lupus-prone MRL/lpr mice (21). Our preliminary data suggest that PI3K activity is also increased in human SLE T cells (>75% of patients, n = 17, in progress). Increased basal PI3K activity may thus constitute a susceptibility factor for SLE, or be required for CD4⁺ memory cell maintenance. Validation of PI3K as a target in systemic lupus, suggested by genetic PI3K interference in this study, is further supported by pharmacological studies using PI3K inhibitors in lupus-prone mice (21).

Chronic inflammatory autoimmune diseases are triggered by distinct factors, including defects in immune response down-regulation as well as central or peripheral tolerance defects, resulting in maintenance of autoreactive CD4⁺ memory cells (22). In the p65^PI3KTg model, lupus is a consequence of excessive CD4⁺ T cell survival (3), resulting in CD4⁺ memory cell accumulation. Recovery from SLE-like disease following PI3K deletion correlates with a reduction in CD4⁺ memory T cell numbers. As pathogenic CD4⁺ memory cells contribute to SLE development (10, 11, 12), the decrease in memory cells is probably a basic mechanism by which PI3K inhibition ameliorates lupus. The decrease in CD4⁺ memory cells with helper activity is probably responsible for the diminished B cell activation, and may reduce macrophage and neutrophil activation. The studies presented nonetheless do not exclude a direct effect of PI3K deletion on these populations.

No differences in disease development were observed between male and female p65^PI3KTg mice (3). As higher female SLE incidence in other models correlates with a higher proportion of pathogenic CD4⁺ cells (10), the observation that the p65^PI3K transgene enhances CD4⁺ cell survival similarly in males and females (3) explains the lack of gender-susceptibility differences. Similarly, PI3K deletion reduced survival of CD4⁺ memory cells in a gender-independent fashion, explaining why both males and females recovered following PI3K deletion.

Regarding specific and redundant I_A and I_B isoform functions, enhanced I_A-PI3K activity compensates the defective pre-TCR-triggered CD4^–CD8^– differentiation and TCR-induced CD4⁺ cell generation in I_B-PI3K^–/– mice. This suggests that the two isoforms cooperate to trigger T cell differentiation (15). Concurring with this, the PI3K^–/– phenotype shows a striking T cell development blockade (23). In this study, we show that both I_A and I_B isoforms regulate CD4⁺ memory cell survival in mature T cells. Comparison of in vitro PI3K^–/– and PI3K^+/– T cell survival supports an independent role for PI3K in CD4⁺ T cell survival. PI3K also regulates T cell activation in vitro and in vivo (14) (our data not shown).

Despite PI3K involvement in T cell activation and survival, the proportion of memory T cells in non-Tg PI3K^+/– and PI3K^–/– mice was similar, suggesting that a homeostatic mechanism compensates the potentially reduced memory cell survival and generation in PI3K^–/– mice. Similar homeostatic correction is found in the PI3K contribution to T cell differentiation. Although defective T cell differentiation is detected in newborn PI3K^–/– mice, T cell populations are near normal in 15-day- to 1-mo-old animals, with only a modest reduction in peripheral CD4⁺ T cell numbers (15).

Our data show that PI3K deficiency reduces CD4⁺ memory T cell survival in p65^PI3KTg mice. Nonetheless, we cannot exclude that one effect of PI3K deletion in this model is a reduction in memory cell generation, as suggested by experiments in MRL/lpr mice (21). In these mice, PI3K inhibition also ameliorates lupus and reduces pathogenic CD4⁺ memory cell numbers (21). In MRL/lpr mice, however, the reduction in CD4⁺ memory T cells is not linked to variations in survival, because apoptosis is defective due to the lpr/Fas mutation (7). The reduction in CD4⁺ memory cells in PI3K inhibitor-treated MRL/lpr mice is thus probably the result from a reduction in memory cell generation.

Although the consequences of PI3K interference are similar regarding lupus amelioration and CD4⁺ memory cell reduction, inhibition of PI3K in MRL/lpr mice reduces hypercellularity more effectively, with a selectively greater effect on the CD4⁺ cell pool (21). Total CD4⁺ T cell numbers are also reduced in PI3K^–/– mice (15). This effect is not seen in PI3K^–/–/p65^PI3KTg mice, however, suggesting that enhanced I_A activation has a unique function in inducing lymphoproliferation that is not counteracted by I_B deficiency.

PI3K is involved in macrophage, neutrophil, and thymocyte migration (13, 14, 15). PI3K deletion, however, did not reduce T cell invasion induced by enhanced I_A-PI3K activity. Accordingly, T cell homing to lymph nodes is only moderately affected by PI3K deletion (24). T cell invasion thus probably involves I_A-PI3K activation through a Tyr kinase pathway, whereas thymus growth may require I_B-PI3K activation through a GPCR. As for I_A and I_B isoform control of T cell activation and survival, either receptors that trigger these responses activate both isoforms, or distinct receptors that activate I_A and I_B, respectively, cooperate in promoting CD4⁺ cell survival and activation.

The results show that whereas I_A isoforms are dominant in the induction of lymphoproliferation and invasion, I_B-PI3K deletion reduces CD4⁺ memory cell survival, even in the presence of active I_A isoforms. As pathogenic CD4⁺ memory cell increase contributes to multigenic murine and human lupus (6, 7, 8, 9, 10, 11, 12), the selective reduction of CD4⁺ memory cells and subsequent amelioration of systemic lupus upon I_B-PI3K deletion suggest that this isoform is a promising target for SLE treatment.

	Acknowledgments

 
We thank M. C. Moreno-Ortíz for cytofluorometry studies; P. Pallares, S. Rodríguez, J. Martín, and L. Gómez for excellent animal work; and C. Mark for editorial assistance.

	Disclosures

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The authors have no financial conflict of interest.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the European Union (QLRT2001-02171), the Community of Madrid (8.3/0030/2000), the Ramon Areces Foundation, and the Spanish Dirección General de Ciencia y Desarrollo Tecnológico (SAF2001.2278). The Department of Immunology and Oncology is supported by the Spanish Council for Scientific Research (Consejo Superior de Investigaciones Cientificas) and by Pfizer. D.F.B. has a Ramón y Cajal contract from the Spanish Ministry of Education and Science.

² Address correspondence and reprint requests to Dr. Ana C. Carrera, Department of Immunology and Oncology, and Animal Facility, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid, Darwin 3, Cantoblanco, Madrid E-28049, Spain. E-mail address: acarrera{at}cnb.uam.es

³ Abbreviations used in this paper: GPCR, G protein-coupled receptor; GN, glomerulonephritis; SLE, systemic lupus erythematosus; Tg, transgenic.

Received for publication July 28, 2005. Accepted for publication October 10, 2005.

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