Polarized cells, polarized views: asymmetric cell division in hematopoietic cells

It has long been recognized that alterations in cell shape and polarity play important roles in coordinating lymphocyte functions. In the last decade, a new aspect of lymphocyte polarity has attracted much attention, termed asymmetric cell division (ACD). ACD has previously been shown to dictate or influence many aspects of development in model organisms such as the worm and the fly, and to be disrupted in disease. Recent observations that ACD also occurs in lymphocytes led to exciting speculations that ACD might influence lymphocyte differentiation and function, and leukemia. Dissecting the role that ACD might play in these activities has not been straightforward, and the evidence to date for a functional role in lymphocyte fate determination has been controversial. In this review, we discuss the evidence to date for ACD in lymphocytes, and how it might influence lymphocyte fate. We also discuss current gaps in our knowledge, and suggest approaches to definitively test the physiological role of ACD in lymphocytes

PTPN2-deficiency exacerbates T follicular helper cell and B cell responses and promotes the development of autoimmunity

Non-coding single nucleotide polymorphisms that repress PTPN2 expression have been linked with the development of type 1 diabetes, rheumatoid arthritis and Crohn's disease. PTPN2 attenuates CD8þ T cell responses to self and prevents overt autoreactivity in the context of T cell homeostasis and antigen crosspresentation. The role of PTPN2 in other immune subsets in the development of autoimmunity remains unclear. Here we show that the inducible deletion of PTPN2 in hematopoietic compartment of adult nonautoimmune prone mice results in systemic inflammation and autoimmunity. PTPN2-deficient mice had increased inflammatory monocytes, B cells and effector T cells in lymphoid and non-lymphoid tissues and exhibited symptoms of dermatitis, glomerulonephritis, pancreatitis and overt liver disease. Autoimmunity was characterised by the formation of germinal centers in the spleen and associated with markedly increased germinal center B cells and T follicular helper (Tfh) cells and circulating anti-nuclear antibodies, inflammatory cytokines and immunoglobulins. CD8þ T cell proliferative responses were enhanced, and interleukin-21-induced STAT-3 signalling in Tfh cells and B cells was increased and accompanied by enhanced B cell proliferation ex vivo. These results indicate that deficiencies in PTPN2 across multiple immune lineages, including naive T cells, Tfh cells and B cells, contribute to the development of autoimmunityThis work was supported by the National Health and Medical Research Council (NHMRC) of Australia (1047055); T.T. is a NHMRC Principal Research Fellow (1103037)

T cell exhaustion and a failure in antigen presentation drive resistance to the graft-versus-leukemia effect

In hematopoietic stem cell transplants, T cells mediate graft-versus-leukemia (GVL), but GVL can fail leading to leukemia relapse. Here the authors use a mouse model in which T cells target the minor histocompatibility antigen H60 to show how this can occur, characterize the CD8+ T cell response and demonstrate how anti-CD40 antibody therapy improves GVL

Polarity proteins in asymmetric cell division during thymocyte development

Reports on established systems to observe cellular and molecular processes that replicate mammalian immune cell development in the thymus. Reports on optimised long term time lapse imaging of immature immune T cells called thymocytes, which will enable visualising and quantifying the temporal and spatial dynamics of proteins that regulate thymocyte cell shape and fate during division

Lethal giant larvae 1 tumour suppressor activity is not conserved in models of mammalian T and B cell leukaemia

In epithelial and stem cells, lethal giant larvae (Lgl) is a potent tumour suppressor, a regulator of Notch signalling, and a mediator of cell fate via asymmetric cell division. Recent evidence suggests that the function of Lgl is conserved in mammalian haematopoietic stem cells and implies a contribution to haematological malignancies. To date, direct measurement of the effect of Lgl expression on malignancies of the haematopoietic lineage has not been tested. In Lgl1-/- mice, we analysed the development of haematopoietic malignancies either alone, or in the presence of common oncogenic lesions. We show that in the absence of Lgl1, production of mature white blood cell lineages and long-term survival of mice are not affected. Additionally, loss of Lgl1 does not alter leukaemia driven by constitutive Notch, c-Myc or Jak2 signalling. These results suggest that the role of Lgl1 in the haematopoietic lineage might be restricted to specific co-operating mutations and a limited number of cellular contexts

Lethal giant larvae-1 deficiency enhances the CD8+ effector T-cell response to antigen challenge in vivo

Lethal giant larvae-1 (Lgl-1) is an evolutionary conserved protein that regulates cell polarity in diverse lineages; however, the role of Lgl-1 in the polarity and function of immune cells remains to be elucidated. To assess the role of Lgl-1 in T cells, we generated chimeric mice with a hematopoietic system deficient for Lgl-1. Lgl-1 deficiency did not impair the activation or function of peripheral CD8 T cells in response to antigen presentation in vitro, but did skew effector and memory T-cell differentiation. When challenged with antigen-expressing virus or tumor, Lgl-1-deficient mice displayed altered T-cell responses. This manifested in a stronger antiviral and antitumor effector CD8 T-cell response, the latter resulting in enhanced control of MC38-OVA tumors. These results reveal a novel role for Lgl-1 in the regulation of virus-specific T-cell responses and antitumor immunity

Characterization of in vivo Dlg1 deletion on T cell development and function.

BackgroundThe polarized reorganization of the T cell membrane and intracellular signaling molecules in response to T cell receptor (TCR) engagement has been implicated in the modulation of T cell development and effector responses. In siRNA-based studies Dlg1, a MAGUK scaffold protein and member of the Scribble polarity complex, has been shown to play a role in T cell polarity and TCR signal specificity, however the role of Dlg1 in T cell development and function in vivo remains unclear.Methodology/principal findingsHere we present the combined data from three independently-derived dlg1-knockout mouse models; two germline deficient knockouts and one conditional knockout. While defects were not observed in T cell development, TCR-induced early phospho-signaling, actin-mediated events, or proliferation in any of the models, the acute knockdown of Dlg1 in Jurkat T cells diminished accumulation of actin at the IS. Further, while Th1-type cytokine production appeared unaffected in T cells derived from mice with a dlg1 germline-deficiency, altered production of TCR-dependent Th1 and Th2-type cytokines was observed in T cells derived from mice with a conditional loss of dlg1 expression and T cells with acute Dlg1 suppression, suggesting a differential requirement for Dlg1 activity in signaling events leading to Th1 versus Th2 cytokine induction. The observed inconsistencies between these and other knockout models and siRNA strategies suggest that 1) compensatory upregulation of alternate gene(s) may be masking a role for dlg1 in controlling TCR-mediated events in dlg1 deficient mice and 2) the developmental stage during which dlg1 ablation begins may control the degree to which compensatory events occur.Conclusions/significanceThese findings provide a potential explanation for the discrepancies observed in various studies using different dlg1-deficient T cell models and underscore the importance of acute dlg1 ablation to avoid the upregulation of compensatory mechanisms for future functional studies of the Dlg1 protein