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Breast cancer is a heterogeneous disease that represents the most common cancer around the world; it comprises 12% of new cases according to the World Health Organization. Despite new approaches in early diagnosis and current treatment, breast cancer is still the leading cause of death for cancer mortality. New targeted therapies against key signalling transduction molecules are required. Phosphoinositide 3-kinase (PI3K) regulates multiple biological functions such as proliferation, survival, migration, and growth. It is well established that PI3K isoform-selective inhibitors show fewer toxic side effects compared to broad spectrum inhibition of PI3K (pan-PI3K inhibitors). Therefore, we tested the PI3K p110δ-selective inhibitor, IC87114, and Vps34-selective inhibitor, Vps34-IN1, on the breast cancer cell lines MCF-7 and MDA-MB-231, representing hormone-responsive and triple-negative breast cancer cells, respectively. Our data show that both inhibitors decreased migration of MCF-7 and MDA-MB-231 cells, and Vps34 also significantly impacted MCF-7 cell proliferation. Three-dimensional (3D) in vitro culture models show that IC87114 and Vps34-IN1 treatment reduced the growth of MCF-7 and MDA-MB-231 cells in 3D tumour spheroid cultures. This study identifies IC87114 and Vps34-IN1 as potential therapeutic approaches in breast cancer. [ABSTRACT FROM AUTHOR]

Activated phosphoinositide 3‐kinase delta syndrome (APDS) is a recently described form of inborn error of immunity (IEI) caused by heterozygous mutations in PIK3CD or PIK3R1 genes, respectively, encoding leukocyte‐restricted catalytic p110δ subunit and the ubiquitously expressed regulatory p85 α subunit of the phosphoinositide 3‐kinase δ (PI3Kδ). The first described patients with respiratory infections, hypogammaglobulinemia with normal to elevated IgM serum levels, lymphopenia, and lymphoproliferation. Since the original description, it is becoming evident that the onset of disease may be somewhat variable over time, both in terms of age at presentation and in terms of clinical and immunological complications. In many cases, patients are referred to various specialists such as hematologists, rheumatologists, gastroenterologists, and others, before an immunological evaluation is performed, leading to delay in diagnosis, which negatively affects their prognosis. The significant heterogeneity in the clinical and immunological features affecting APDS patients requires awareness among clinicians since good results with p110δ inhibitors have been reported, certainly ameliorating these patients' quality of life and prognosis. [ABSTRACT FROM AUTHOR]

Activated phosphoinositide 3‐kinase delta syndrome (APDS) is a recently described form of inborn error of immunity (IEI) caused by heterozygous mutations in PIK3CD or PIK3R1 genes, respectively, encoding leukocyte‐restricted catalytic p110δ subunit and the ubiquitously expressed regulatory p85 α subunit of the phosphoinositide 3‐kinase δ (PI3Kδ). The first described patients with respiratory infections, hypogammaglobulinemia with normal to elevated IgM serum levels, lymphopenia, and lymphoproliferation. Since the original description, it is becoming evident that the onset of disease may be somewhat variable over time, both in terms of age at presentation and in terms of clinical and immunological complications. In many cases, patients are referred to various specialists such as hematologists, rheumatologists, gastroenterologists, and others, before an immunological evaluation is performed, leading to delay in diagnosis, which negatively affects their prognosis. The significant heterogeneity in the clinical and immunological features affecting APDS patients requires awareness among clinicians since good results with p110δ inhibitors have been reported, certainly ameliorating these patients' quality of life and prognosis. [ABSTRACT FROM AUTHOR]

Phosphoinositide 3-kinase p110 delta (PI3K p110δ) is pivotal for CD8+ T cell immune responses. The current study explores PI3K p110δ induction and repression of antigen receptor and cytokine regulated programs to inform how PI3K p110δ directs CD8+ T cell fate. The studies force a revision of the concept that PI3K p110δ controls metabolic pathways in T cells and reveal major differences in PI3K p110δ regulated transcriptional programs between naïve and effector cytotoxic T cells (CTL). These differences include differential control of the expression of cytolytic effector molecules and costimulatory receptors. Key insights from the work include that PI3K p110δ signalling pathways repress expression of the critical inhibitory receptors CTLA4 and SLAMF6 in CTL. Moreover, in both naïve and effector T cells the dominant role for PI3K p110δ is to restrain the production of the chemokines that orchestrate communication between adaptive and innate immune cells. The study provides a comprehensive resource for understanding how PI3K p110δ uses multiple processes mediated by Protein Kinase B/AKT, FOXO1 dependent and independent mechanisms and mitogen-activated protein kinases (MAPK) to direct CD8+ T cell fate. [ABSTRACT FROM AUTHOR]

Phosphoinositide 3-kinases (PI3Ks) play a central role in adaptive immunity by transducing signals from the T cell antigen receptor (TCR) via production of PIP3. PI3Kδ is a heterodimer composed of a p110δ catalytic subunit associated with a p85α or p85β regulatory subunit and is preferentially engaged by the TCR upon T cell activation. The molecular mechanisms leading to PI3Kδ recruitment and activation at the TCR signalosome remain unclear. In this study, we have used quantitative mass spectrometry, biochemical approaches and CRISPR-Cas9 gene editing to uncover the p110δ interactome in primary CD4+ T cells. Moreover, we have determined how the PI3Kδ interactome changes upon the differentiation of small naïve T cells into T cell blasts expanded in the presence of IL-2. Our interactomic analyses identified multiple constitutive and inducible PI3Kδ-interacting proteins, some of which were common to naïve and previously-activated T cells. Our data reveals that PI3Kδ rapidly interacts with as many as seven adaptor proteins upon TCR engagement, including the Gab-family proteins, GAB2 and GAB3, a CD5-CBL signalosome and the transmembrane proteins ICOS and TRIM. Our results also suggest that PI3Kδ pre-forms complexes with the adaptors SH3KBP1 and CRKL in resting cells that could facilitate the localization and activation of p110δ at the plasma membrane by forming ternary complexes during early TCR signalling. Furthermore, we identify interactions that were not previously known to occur in CD4+ T cells, involving BCAP, GAB3, IQGAP3 and JAML. We used CRISPR-Cas9-mediated gene knockout in primary T cells to confirm that BCAP is a positive regulator of PI3K-AKT signalling in CD4+ T cell blasts. Overall, our results provide evidence for a large protein network that regulates the recruitment and activation of PI3Kδ in T cells. Finally, this work shows how the PI3Kδ interactome is remodeled as CD4+ T cells differentiate from naïve T cells to activated T cell blasts. These activated T cells upregulate additional PI3Kδ adaptor proteins, including BCAP, GAB2, IQGAP3 and ICOS. This rewiring of TCR-PI3K signalling that occurs upon T cell differentiation may serve to reduce the threshold of activation and diversify the inputs for the PI3K pathway in effector T cells. [ABSTRACT FROM AUTHOR]

Phosphoinositide 3-kinase catalytic subunit δ isoform (P110δ) is mainly expressed in white blood cells. It is involved in T and B lymphocyte differentiation, maturation and the neutrophil chemotaxis process. Apolipoprotein E (ApoE) is an arginine-rich alkaline protein, which is present in plasma chylomicron, low-density lipoprotein and very low-density lipoprotein. The present study aimed to determine the effects of P110δ deletion on myocarditis in ApoE−/− mice. A mouse model of ApoE and P110δ double deletion was initially constructed; hematoxylin and eosin (H&E) staining was performed to detect the histological alterations in the mouse myocardium. Systolic and diastolic alterations, and alterations in the left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF) were examined by electrocardiogram. Blood cell of ApoE and P110δ double mice was used to detect changes in white blood cells and monocytes. Western blotting was used to detect the expression levels of apoptosis-associated proteins, whereas flow cytometry was used to detect the percentage of apoptosis. Morphological alterations in myocardial cells were observed under a microscope. The results of polymerase chain reaction demonstrated that double deletion mice were successfully constructed. H&E staining revealed that cells in the ApoE−/− mice were spindle-shaped; however, the nuclei were smaller in the double deletion mice. There was no change in cardiac contraction in normal mice; however, in double deletion mice, the systolic and diastolic contractions were markedly reduced. LVFS and LVEF were decreased compared with in the control group. Blood cell analysis indicated that the content of white blood cells and monocytes in the experimental group was significantly higher than that in the control group. Western blotting demonstrated that the expression levels of apoptotic proteins in double deletion mice were significantly higher compared with in the control group. Flow cytometry revealed that the apoptotic ratio was increased in double deletion mice compared with in the control group (42 vs. 21%). These findings suggested that deletion of P110δ may induce monocyte peritoneal infiltration and increase apoptosis, thus promoting the development of myocarditis. [ABSTRACT FROM AUTHOR]

Activity and expression of the phosphoinositide 3-kinase (PI3K) catalytic isoform, PIK3CD/p110δ, is increased in schizophrenia, autism, and intellectual delay and pro-cognitive preclinical efficacy of p110δ-inhibition has been demonstrated in pharmacological, genetic, and developmental rodent models of psychiatric disorders. Although PI3K signaling has been implicated in the development and function of neurons and glia; isoform-specific roles of the individual PI3Ks are less clear and the biological effects of increased p110δ on neuronal development are unknown. Since the pathobiological direction of p110δ changes in neurodevelopmental disorders are increased expression and activity, we hypothesized that overexpression of p110δ would impact measures of neuronal development and maturation relevant to connectivity and synaptic transmission. p110δ overexpression in primary rat hippocampal cultures significantly reduced dendritic morphogenesis and arborization and increased immature and mature dendritic spine densities, without impacting cell viability, soma size, or axon length. Together, our novel findings demonstrate the importance of homeostatic regulation of the p110δ isoform for normative neuronal development and highlight a potential pathophysiological mechanism of association to disorders of neurodevelopment. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a uniformly fatal disorder of B cells characterized by the accumulation of abnormal plasma cells. Phosphoinositide 3-kinase (PI3K) signaling pathways play a critical regulatory role in MM pathology. Copanlisib, also known as BAY80-6946, is a potent PI3Kα and δ inhibitor. In this study, we investigated the efficacy of copanlisib and a proteasome inhibitor using MM cell lines and primary samples. The p110α and δ catalytic subunits of the class PI3K increased, and carfilzomib activity reduced in the presence of a supernatant from the feeder cell line, HS-5. Phosphorylation of Akt and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) partially reduced upon carfilzomib treatment in the presence of HS-5. Apoptosis also decreased. Copanlisib treatment for 72 h inhibited growth in MM cell lines and induced apoptosis. Combination treatment of MM cells with carfilzomib and copanlisib caused greater cytotoxicity than that caused by either drug alone and increased apoptosis. Caspase 3 activity increased while that of Akt decreased after combination treatment with copanlisib and carfilzomib. Further, copanlisib inhibited vascular endothelial growth factor (VEGF)-mediated angiogenesis in vitro and in vivo. It also inhibited C-X-C motif chemokine 12 (CXCL12)-mediated chemotaxis. The data suggest that administration of the PI3K inhibitor, copanlisib, may be a powerful strategy against stroma-associated drug resistance of MM cells and can enhance the cytotoxic effects of proteasome inhibitors in such residual MM cells. [ABSTRACT FROM AUTHOR]

Pathogenic gain-of-function mutations in the gene encoding phosphoinositide 3-kinase delta (PI3Kδ) cause activated PI3Kδ syndrome (APDS), a disease characterized by humoral immunodeficiency, lymphadenopathy, and an inability to control persistent viral infections including Epstein–Barr virus (EBV) and cytomegalovirus (CMV) infections. Understanding the mechanisms leading to impaired immune response is important to optimally treat APDS patients. Immunosenescence of CD8+ T cells was suggested to contribute to APDS pathogenesis. However, the constitutive activation of T cells in APDS may also result in T cell exhaustion. Therefore, we studied exhaustion of the CD8+ T cell compartment in APDS patients and compared them with healthy controls and HIV patients, as a control for exhaustion. The subset distribution of the T cell compartment of APDS patients was comparable with HIV patients with decreased naive CD4+ and CD8+ T cells and increased effector CD8+ T cells. Like in HIV+ patients, expression of activation markers and inhibitory receptors CD160, CD244, and programmed death receptor (PD)-1 on CD8+ T cells was increased in APDS patients, indicating exhaustion. EBV-specific CD8+ T cells from APDS patients exhibited an exhausted phenotype that resembled HIV-specific CD8+ T cells in terms of inhibitory receptor expression. Inhibition of PD-1 on EBV-specific CD8+ T cells from APDS patients enhanced in vitro proliferation and effector cytokine production. Based on these results, we conclude that total and EBV-specific CD8+ T cells from APDS patients are characterized by T cell exhaustion. Furthermore, PD-1 checkpoint inhibition may provide a possible therapeutic approach to support the immune system of APDS patients to control EBV and CMV. [ABSTRACT FROM AUTHOR]

Background: Dysfunctions in the PI3K/mTOR pathway have gained a lot of attention in autism research. This was initially based on the discovery of several monogenic autism spectrum disorders with mutations or defects in PI3K/ mTOR signaling components. Recent genetic studies corroborate that defective PI3K/mTOR signaling might be a shared pathomechanism in autism disorders of so far unknown etiology, but functional molecular analyses in human cells are rare. The goals of this study were to perform a functional screen of cell lines from patients with idiopathic autism for defects in PI3K/mTOR signaling, to test if further functional analyses are suitable to detect underlying molecular mechanisms, and to evaluate this approach as a biomarker tool to identify therapeutic targets. Methods: We performed phospho-S6- and S6-specific ELISA experiments on 21 lymphoblastoid cell lines from the AGRE collection and on 37 lymphoblastoid cell lines from the Simons Simplex Collection and their healthy siblings. Cell lines from one individual with increased S6 phosphorylation and his multiplex family were analyzed in further detail to identify upstream defects in PI3K signaling associated with autism diagnosis. Results: We detected significantly increased S6 phosphorylation in 3 of the 21 lymphoblastoid cell lines from AGRE compared to a healthy control and in 1 of the 37 lymphoblastoid cell lines from the Simons Simplex Collection compared to the healthy sibling. Further analysis of cells from one individual with elevated S6 phosphorylation showed increased expression of the PI3K catalytic subunit p110δ, which was also observed in lymphoblastoid cells from other autistic siblings but not unaffected members in his multiplex family. The p110δ-selective inhibitor IC87114 reduced elevated S6 phosphorylation and protein synthesis in this cell line. Conclusions: Our results suggest that functional analysis of PI3K/mTOR signaling is a biomarker tool to identify disease-associated molecular defects that could serve as therapeutic targets in autism. Using this approach, we discovered impaired signaling and protein synthesis through the PI3K catalytic subunit p110δ as an underlying molecular defect and potential treatment target in select autism spectrum disorders. Increased p110δ activity was recently associated with schizophrenia, and our results suggest that p110δ may also be implicated in autism. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease accompanying excessive inflammatory responses. Phosphoinositide 3-kinase p110δ (PI3Kδ) is reported to associate with autoimmune conditions. We here aimed to determine whether selective inhibition of PI3Kδ is effective in a lupus model of BXSB mice, using the selective PI3Kδ inhibitor IC87114, which was intraperitoneally administrated to BXSB mice aged from 14 to 22 weeks. We showed that IC87114 improved renal function by decreasing the levels of proteinuria and serum creatinine, ameliorating the pathologic changes of kidneys and IgG and C3 deposition. Serum anti-autoantibody to nuclear antigen, anti-dsDNA, IL-1β, and IL-17 were markedly reduced by IC87114 therapy. Hepatic damage was also inhibited by administration of IC87114. Expression of phosphorylated AKT (p-AKT) and monocyte chemoattractant protein-1 was inhibited and mouse survival improved. In sum, PI3Kδ activation may be a critical factor for escalating autoimmune renal and hepatic damage, and its inhibition may alleviate the autoimmune damage. Our study reveals that the selective blockade of PI3Kδ is effective for mouse SLE. [ABSTRACT FROM AUTHOR]

Alterations in the PI3K/Akt pathway, a pathway that promotes proliferation and oncogenic transformation, are common in various cancers. In neuroblastoma, activation of Akt is correlated with aggressive disease although mutations in genes of this pathway are rare. Previous findings include a few mutations in PIK3CD, the gene encoding PI3K catalytic subunit delta, p110δ. We recently reported that an alternatively spliced form of p110δ, called p37δ, had cell proliferative properties and was over-expressed in ovarian and colorectal tumors. Here, we investigated p37δ in neuroblastoma primary tumors of different stages using qPCR (TaqMan) for gene expression analysis (46 samples) and Western blot for protein analysis (22 samples). Elevated levels of both p37δ-mRNA and p110δ-mRNA were detected in metastasizing neuroblastoma tumors compared to normal adrenal gland ( P < 0.05), and higher expression of p37δ-mRNA relative to p110δ-mRNA in neuroblastoma non-survivor patients compared to survivors ( P < 0.01). p37δ-Protein levels but not p110δ levels correlated with increased pAKT T308 and pERK levels. The p37δ-mRNA levels did not correlate with the protein levels, indicating major regulation at the translational/protein level. Deregulation of signaling pathways is a hallmark of cancer development. Here, we show that p37δ, a kinase-dead isoform of the PI3K catalytic subunit p110δ, is over-expressed in neuroblastoma tumors, and that it correlates with the activation of both PI3K/Akt- and RAS-signaling pathways. [ABSTRACT FROM AUTHOR]

B-cell receptor (BCR) signaling is essential for normal B-cell development, selection, survival, proliferation, and differentiation into antibody-secreting cells. Similarly, this pathway plays a key role in the pathogenesis of multiple B-cell malignancies. Genetic and pharmacological approaches have established an important role for the Spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk), and phosphatidylinositol 3-kinase isoform p110delta (PI3Kδ) in coupling the BCR and other BCRs to B-cell survival, migration, and activation. In the past few years, several small-molecule inhibitory drugs that target PI3Kδ, Btk, and Syk have been developed and shown to have efficacy in clinical trials for the treatment of several types of B-cell malignancies. Emerging preclinical data have also shown a critical role of BCR signaling in the activation and function of self-reactive B cells that contribute to autoimmune diseases. Because BCR signaling plays a major role in both B-cell-mediated autoimmune inflammation and B-cell malignancies, inhibition of this pathway may represent a promising new strategy for treating these diseases. This review summarizes recent achievements in the mechanism of action, pharmacological properties, and clinical activity and toxicity of these BCR signaling inhibitors, with a focus on their emerging role in treating lymphoid malignancies and autoimmune disorders. [ABSTRACT FROM AUTHOR]

Colony stimulating factor-1 (CSF-1) and its receptor (CSF-1R) are key regulators of macrophage biology, and their elevated expression in cancer cells has been linked to poor prognosis. CSF-1Rs are thought to function at the plasma membrane. We show here that functional CSF-1Rs are present at the nuclear envelope of various cell types, including primary macrophages, human cancer cell lines, and primary human carcinomas. In response to CSF-1, added to intact cells or isolated nuclei, nucleus-associated CSF-1R became phosphorylated and triggered the phosphorylation of Akt and p27 inside the nucleus. Extracellularly added CSF-1 was also found to colocalize with nucleus-associated CSF-1Rs. All these activities were found to depend selectively on the activity of the p110δ isoform of phosphoinositide 3-kinase (PI3K). This finding was related to the p110δ-dependent translocation of exogenous CSF-1 to the nucleus-associated CSF-1Rs, correlating with a prominent role of p110δ in activation of the Rab5 GTPase, a key regulator of the endocytic trafficking. siRNA-silencing of Rab5a phenocopied p110δ inactivation and nuclear CSF-1 signaling. Our work demonstrates for the first time the presence of functional nucleus-associated CSF-1Rs, which are activated by extracellular CSF-1 by a mechanism that involves p110δ and Rab5 activity. These findings may have important implications in cancer development. [ABSTRACT FROM AUTHOR]

We have investigated the function of the p110d catalytic subunit of phosphoinositide 3-kinase (PI 3-kinase) in platelets using p110d knock-out (p110d –/– ) mice and p110d knock-in (p110d D910A/D910A ) mice, which express a catalytically inactive form of the enzyme. Aggregation to threshold concentrations of the GPVI-specific agonist, CRP, was partially reduced in p110d –/– and p110d D910A/D910A platelets. This inhibition was overcome by higher concentrations of CRP. The degree of inhibition was considerably weaker than that induced by LY294002 and wortmannin, which inhibit all isoforms of PI 3-kinase. p110d –/– platelets showed decreased spreading on fibrinogen- or von Willebrand factor (VWF)-coated surfaces under static conditions, whereas they spread normally on collagen. LY294002 had a more pronounced inhibitory effect on spreading on all three surfaces. Adhesion and aggregate formation of p110d –/– platelets to collagen or fibrinogen/VWF at intermediate/high rates of shear were normal. This study demonstrates a minor role for the p110d catalytic subunit in mediating platelet activation by the collagen receptor GPVI and integrin aIIbß3. The more pronounced inhibitory effect of LY294002 and wortmannin indicates that other isoforms of PI 3-kinase play a more significant role in signalling by the two platelet glycoprotein receptors. [ABSTRACT FROM AUTHOR]

Activated phosphoinositide 3-kinase delta syndrome 1 (APDS-1) is a recently described inborn error of immunity caused by monoallelic gain-of-function mutations in the PIK3CD gene. We reviewed for the first time medical records and laboratory data of eight Italian APDS-1 patients. Recurrent sinopulmonary infections were the most common clinical feature at onset of disease. Seven patients presented lymphoproliferative disease, at onset or during follow-up, one of which resembled hemophagocytic lymphohistiocytosis (HLH). Genetic analysis of the PIK3CD gene revealed three novel mutations: functional testing confirmed their activating nature. In the remaining patients, the previously reported variants p.E1021K (n = 4) and p.E525A (n = 1) were identified. Six patients were started on immunoglobulin replacement treatment (IgRT). One patient successfully underwent hematopoietic stem cell transplantation (HSCT), with good chimerism and no GVHD at 21 months post-HSCT. APDS-1 is a combined immune deficiency with a wide variety of clinical manifestations and a complex immunological presentation. Besides IgRT, specific therapies targeting the PI3Kδ pathway will most likely become a valid aid for the amelioration of patients' clinical management and their quality of life. [ABSTRACT FROM AUTHOR]

Intracellular reactive oxygen species (ROS) play an important role in the proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs). HSPCs are difficult to be expanded ex vivo while maintaining their stemness when they are exposed to oxidative damage after being released from the bone marrow. There have been efforts to overcome this limitation by using various cytokine cocktails and antioxidants. In this study, we investigated the effects of echinochrome A (Ech A)-a well-established and non-toxic antioxidant-on the ex vivo expansion of HSPCs by analyzing a CD34+ cell population and their biological functions. We observed that Ech A-induced suppression of ROS generation and p38-MAPK/JNK phosphorylation causes increased expansion of CD34+ cells. Moreover, p38-MAPK/JNK inhibitors SB203580 and SP600125 promoted ex vivo expansion of CD34+ cells. We also demonstrated that the activation of Lyn kinase and p110δ is a novel mechanism for Ech A to enhance ex vivo expansion of CD34+ cells. Ech A upregulated phospho-Src, phospho-Lyn, and p110δ expression. Furthermore, the Ech A-induced ex vivo expansion of CD34+ cells was inhibited by pretreatment with the Src family inhibitor PP1 and p110δ inhibitor CAL-101; PP1 blocked p110δ upregulation and PI3K/Akt activation, whereas CAL-101 and PI3K/Akt pathway inhibitor LY294002 did not block Src/Lyn activation. These results suggest that Ech A initially induces Src/Lyn activation, upregulates p110δ expression, and finally activates the PI3K/Akt pathway. CD34+ cells expanded in the presence of Ech A produced equal or more hematopoietic colony-forming cells than unexpanded CD34+ cells. In conclusion, Ech A promotes the ex vivo expansion of CD34+ cells through Src/Lyn-mediated p110δ expression, suppression of ROS generation, and p38-MAPK/JNK activation. Hence, Ech A is a potential candidate modality for the ex vivo, and possibly in vivo, expansion of CD34+ cells. [ABSTRACT FROM AUTHOR]

PI3Ks display integrant significance in T-cell development and differentiation, which is related to host defense against infections. Here, we investigated the role of p110δ isoform of PI3Ks in host defense against chlamydial lung infection in a mouse model. Our data showed that lung infection with Chlamydia muridarum (Cm) activated PI3K/AKT signaling pathway. Compared to WT mice, p110δD910A mice, mice with an inactivating knockin mutation in the p110δ Isoform of PI3Ks, showed more sever disease phenotype and slower recovery, which was associated with reduced Chlamydia- specific Th1 and Th17 immune responses following infection. Further adoptive transfer experiment showed that mice which received CD4+ T cells from infected p110δD910A mice exhibited greater body weight loss and higher bacterial loads in the lung than those which received CD4+ T cells from WT mice following challenge infection. These results provide in vivo evidence that p110δ isoform of PI3Ks plays an important role in host defense against chlamydial infection by promoting CD4+ T-cell immunity. [ABSTRACT FROM AUTHOR]