In multicellular organisms, homeostasis is maintained through a balance between cell proliferation and cell death. Although much is known about the control of cell proliferation, less is known about the control of cell death. Physiologic cell death occurs primarily through an evolutionarily conserved form of cell suicide termed apoptosis. The decision of a cell to undergo apoptosis can be influenced by a wide variety of regulatory stimuli. Recent evidence suggests that alterations in cell survival contribute to the pathogenesis of a number of human diseases, including cancer, viral infections, autoimmune diseases, neurodegenerative disorders, and AIDS (acquired immunodeficiency syndrome). Treatments designed to specifically alter the apoptotic threshold may have the potential to change the natural progression of some of these diseases.

https://science.sciencemag.org/content/sci/267/5203/1456.full.pdf

Apoptosis in the pathogenesis and treatment of disease

The classical pathway of interferon-gamma-dependent activation of macrophages by T helper 1 (T(H)1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the T(H)2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.

Alternative activation of macrophages

Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response.

Two subsets of memory T lymphocytes with distinct homing potentials and effector functions

Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells. Various cells express Fas, whereas FasL is expressed predominantly in activated T cells. In the immune system, Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction.

https://science.sciencemag.org/content/sci/267/5203/1449.full.pdf

The Fas Death Factor

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)71142-9.pdf

Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.

In vitro, T cell-dependent cytotoxicity is mediated by two distinct mechanisms, one being perforin-, the other Fas-dependent. The contribution of both of these mechanisms to clearance of viral infections was investigated in mice for the non-cytopathic lymphocytic choriomeningitis virus (LCMV) and the cytopathic vaccinia, vesicular stomatitis (VSV) and Semliki forest (SFV) viruses. Clearance of an acute LCMV infection was mediated by the perforin-dependent mechanism without measurable involvement of the Fas-dependent pathway. For the resolution of vaccinia virus infection and for resistance against VSV and SFV, however, neither of the two pathways was required. These data suggest that perforin-dependent cytotoxicity mediated by T cells is crucial for protection against non-cytopathic viruses, whereas infections with cytopathic viruses are controlled by nonlytic T cell-dependent soluble mediators such as cytokines (IFN-gamma against vaccinia virus) and neutralizing antibodies (against VSV and SFV).

The roles of perforin- and Fas-dependent cytotoxicity in protection against cytopathic and noncytopathic viruses.

IL-4 receptor α-chain-deficient (IL-4Rα −/− ) mice were generated by homologous and site-specific recombination, using the Cre/loxP system in BALB/c-derived embryonic stem cells. In vitro analysis of cells from these mice revealed impaired IL-4- and IL-13-mediated functions, demonstrating that the IL-4Rα-chain is an essential component of both the IL-4 and the IL-13 receptor. Whereas Leishmania major -infected BALB/c mice developed fatal progressive disease with type 2 Ab responses within 3 mo, both IL-4Rα −/− and IL-4 −/− BALB/c mice contained infection with reduced footpad swelling, parasite load, moderate histopathology, and type 1 Ab responses during this time period. Conclusively, these results demonstrate an IL-4-dependent mechanism of susceptibility in BALB/c mice. Nevertheless, in contrast to mutant mice, infected C57BL/6 mice healed completely within 3 mo, indicating that additional factors are necessary for subsequent healing and elimination of the pathogen. During the further course of infection, IL-4Rα −/− mice developed progressive disease with massive footpad swelling. Lesions became ulcerative and necrotic with subsequent destruction of connective tissue and bones, as well as dissemination into organs and consequent mortality within the monitored 6 mo of chronic infection. In striking contrast, IL-4 −/− mice maintained control of infection on a moderate level, but were unable to clear the pathogen. The distinct phenotypes of the BALB/c embryonic stem cell-derived IL-4 −/− and IL-4Rα −/− mouse strains identify previously unsuspected mechanisms for maintaining host immunity to chronic infection with L. major , mediated by a functional IL-13 receptor.

Differences between IL-4- and IL-4 receptor alpha-deficient mice in chronic leishmaniasis reveal a protective role for IL-13 receptor signaling.

Growth of Listeria monocytogenes is mainly controlled by macrophages, which are activated by specific T cells. A potential role of CD8+ T cells by direct lysis of infected cells was investigated in perforin-deficient mice generated by homologous recombination. The absence of perforin-mediated cytotoxicity resulted in delayed clearance of Listeria from the spleen but not the liver after primary infection, overall susceptibility to Listeria however was not increased. Protection against a secondary infection was drastically impaired in perforin-deficient mice. Adoptive transfer of immune spleen cells to recipients revealed that anti-Listeria protection by CD8+ T cells from perforin-deficient versus normal mice was about 10-fold reduced in livers and about 100-fold reduced in the spleen of recipients. CD4+ T cells from immune control and perforin-deficient mice conferred comparable protection. These results indicate that the protective effect of CD8+ T cells against an intracellular bacterium mainly evident in secondary infection is mediated by a perforin-dependent pathway, presumably cytotoxicity, and less by other direct or indirect effector mechanisms.

CD8+ T cell‐mediated protection against an intracellular bacterium by perforin‐dependent cytotoxicity

Establishment of a germ-line competent C57BL/6 embryonic stem cell line.

The agent that causes prion diseases is thought to be identical with PrPSc, a conformer of the normal prion protein PrPC. PrPC-deficient mice do not exhibit major pathologies, perhaps because they express a protein termed Dpl, which shares significant biochemical and structural homology with PrPC. To investigate the physiological function of Dpl, we generated mice harbouring a homozygous disruption of the Prnd gene that encodes Dpl. Dpl deficiency did not interfere with embryonic and postnatal development, but resulted in male sterility. Dpl protein was expressed at late stages of spermiogenesis, and spermatids of Dpl mutants were reduced in numbers, immobile, malformed and unable to fertilize oocytes in vitro. Mechanical dissection of the zona pellucida partially restored in vitro fertilization. We conclude that Dpl regulates male fertility by controlling several aspects of male gametogenesis and sperm–egg interaction.

/pdf/absence-of-the-prion-protein-homologue-doppel-causes-male-5aa69ick1g.pdf

Birgit Ledermann

Papers

The roles of perforin- and Fas-dependent cytotoxicity in protection against cytopathic and noncytopathic viruses.

Differences between IL-4- and IL-4 receptor alpha-deficient mice in chronic leishmaniasis reveal a protective role for IL-13 receptor signaling.

CD8+ T cell‐mediated protection against an intracellular bacterium by perforin‐dependent cytotoxicity

Establishment of a germ-line competent C57BL/6 embryonic stem cell line.

Absence of the prion protein homologue Doppel causes male sterility