Showing papers by "Lewis L. Lanier published in 2018"

A human anti-IL-2 antibody that potentiates regulatory T cells by a structure-based mechanism.

Abstract: Interleukin-2 (IL-2) has been shown to suppress immune pathologies by preferentially expanding regulatory T cells (Tregs). However, this therapy has been limited by off-target complications due to pathogenic cell expansion. Recent efforts have been focused on developing a more selective IL-2. It is well documented that certain anti-mouse IL-2 antibodies induce conformational changes that result in selective targeting of Tregs. We report the generation of a fully human anti-IL-2 antibody, F5111.2, that stabilizes IL-2 in a conformation that results in the preferential STAT5 phosphorylation of Tregs in vitro and selective expansion of Tregs in vivo. When complexed with human IL-2, F5111.2 induced remission of type 1 diabetes in the NOD mouse model, reduced disease severity in a model of experimental autoimmune encephalomyelitis and protected mice against xenogeneic graft-versus-host disease. These results suggest that IL-2-F5111.2 may provide an immunotherapy to treat autoimmune diseases and graft-versus-host disease.

Human antimicrobial cytotoxic T lymphocytes, defined by NK receptors and antimicrobial proteins, kill intracellular bacteria

Abstract: Human CD8+ cytotoxic T lymphocytes (CTLs) contribute to antimicrobial defense against intracellular pathogens through secretion of cytotoxic granule proteins granzyme B, perforin, and granulysin. However, CTLs are heterogeneous in the expression of these proteins, and the subset(s) responsible for antimicrobial activity is unclear. Studying human leprosy, we found that the subset of CTLs coexpressing all three cytotoxic molecules is increased in the resistant form of the disease, can be expanded by interleukin-15 (IL-15), and is differentiated from naive CD8+ T cells by Langerhans cells. RNA sequencing analysis identified that these CTLs express a gene signature that includes an array of surface receptors typically expressed by natural killer (NK) cells. We determined that CD8+ CTLs expressing granzyme B, perforin, and granulysin, as well as the activating NK receptor NKG2C, represent a population of "antimicrobial CTLs" (amCTLs) capable of T cell receptor (TCR)-dependent and TCR-independent release of cytotoxic granule proteins that mediate antimicrobial activity.

Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? NK Cell Memory and Immunization Strategies against Infectious Diseases and Cancer.

Abstract: Immunological memory is an evolutionary adaptation of the vertebrate immune system that protects the host from repeated pathogen infection. T and B cells possess the specificity and longevity required to generate immune memory, whereas natural killer (NK) cells make up a component of the immune system that was not thought to possess these features. However, much evidence from the last decade has challenged this dogma. The investigators were asked to address the following questions: Is there NK cell memory? And can NK cell memory be harnessed for vaccination? Thus, this article explores the recent literature showing immune memory in NK cells. Along with highlighting these studies, we speculate how NK cell memory can be harnessed in immunization strategies against infectious diseases and cancer.

Natural killers join the fight against cancer

Abstract: Immunotherapy represents one of the major breakthroughs in the treatment of cancer patients. Current therapies focus on harnessing the adaptive immune system, with great success achieved by interfering with immune checkpoints to unleash antitumor CD8+ T cell responses. There is emerging evidence that cancers develop multiple strategies to escape CD8+ T cell recognition. These tumors, however, can be preferentially attacked by natural killer (NK) cells. NK cells are innate lymphocytes that express activating receptors, including the NK group 2D (NKG2D) receptor, which recognize ligands displayed on the surface of tumor cells and pathogen-infected cells. On page 1537 of this issue, Ferrari de Andrade et al. ( 1 ) present an elegant approach to improve NK cell recognition of tumor cells, extending the range of immunotherapies beyond T cells.

Recognition of host Clr-b by the inhibitory NKR-P1B receptor provides a basis for missing-self recognition.

Abstract: The interaction between natural killer (NK) cell inhibitory receptors and their cognate ligands constitutes a key mechanism by which healthy tissues are protected from NK cell-mediated lysis. However, self-ligand recognition remains poorly understood within the prototypical NKR-P1 receptor family. Here we report the structure of the inhibitory NKR-P1B receptor bound to its cognate host ligand, Clr-b. NKR-P1B and Clr-b interact via a head-to-head docking mode through an interface that includes a large array of polar interactions. NKR-P1B:Clr-b recognition is extremely sensitive to mutations at the heterodimeric interface, with most mutations severely impacting both Clr-b binding and NKR-P1B receptor function to implicate a low affinity interaction. Within the structure, two NKR-P1B:Clr-b complexes are cross-linked by a non-classic NKR-P1B homodimer, and the disruption of homodimer formation abrogates Clr-b recognition. These data provide an insight into a fundamental missing-self recognition system and suggest an avidity-based mechanism underpins NKR-P1B receptor function.

Crk Adaptor Proteins Regulate NK Cell Expansion and Differentiation during Mouse Cytomegalovirus Infection.

Abstract: Natural killer cells are critical in the immune response to infection and malignancy. Prior studies have demonstrated that Crk family proteins can influence cell apoptosis, proliferation, and cell transformation. In this study, we investigated the role of Crk family proteins in mouse NK cell differentiation and host defense using a mouse CMV infection model. The number of NK cells, maturational state, and the majority of the NKR repertoire was similar in Crk x Crk-like (CrkL)-double-deficient and wild type NK cells. However, Crk family proteins were required for optimal activation, IFN-γ production, expansion, and differentiation of Ly49H+ NK cells, as well as host defense during mouse CMV infection. The diminished function of Crk x CrkL-double-deficient NK cells correlated with decreased phosphorylation of STAT4 and STAT1 in response to IL-12 and IFN-α stimulation, respectively. Together, our findings analyzing NK cell-specific Crk-deficient mice provide insights into the role of Crk family proteins in NK cell function and host defense.

Pillars Article: Activation of NK Cells and T Cells by NKG2D, a Receptor for Stress-Inducible MICA. Science. 1999. 285: 727-729.

Abstract: Author(s): Bauer, Stefan; Groh, Veronika; Wu, Jun; Steinle, Alexander; Phillips, Joseph H; Lanier, Lewis L; Spies, Thomas

Memory T Cell Proliferation before Hepatitis C Virus Therapy Predicts Antiviral Immune Responses and Treatment Success.

Abstract: The contribution of the host immune system to the efficacy of new anti-hepatitis C virus (HCV) drugs is unclear. We undertook a longitudinal prospective study of 33 individuals with chronic HCV treated with combination pegylated IFN-α, ribavirin, and telaprevir/boceprevir. We characterized innate and adaptive immune cells to determine whether kinetics of the host response could predict sustained virologic response (SVR). We show that characteristics of the host immune system present before treatment were correlated with successful therapy. Augmentation of adaptive immune responses during therapy was more impressive among those achieving SVR. Most importantly, active memory T cell proliferation before therapy predicted SVR and was associated with the magnitude of the HCV-specific responses at week 12 after treatment start. After therapy initiation, the most important correlate of success was minimal monocyte activation, as predicted by previous in vitro work. In addition, subjects achieving SVR had increasing expression of the transcription factor T-bet, a driver of Th1 differentiation and cytotoxic effector cell maturation. These results show that host immune features present before treatment initiation predict SVR and eventual development of a higher frequency of functional virus-specific cells in blood. Such host characteristics may also be required for successful vaccine-mediated protection.

The Contribution of Natural Killer and T-Cells to the Lymphokine-Activated Killer Cell Phenomenon

Abstract: In vitro culture of lymphocytes in interleukin-2 (IL-2) results in the generation of cytotoxic cells that lyse a broad spectrum of solid tumors, as well as hematopoietic cell tumors, without deliberate immunization. Peripheral blood is the source for lymphocytes used in human Lymphokine-activated killer (LAK) immunotherapy. The predominant effectors of LAK activity in peripheral blood are Natural killer (NK) cells, as defined by cells expressing CD 16 and/or Leu 19, but lacking expression of CD3. The predominant effectors of LAK activity in peripheral blood are NK cells, as defined by cells expressing CD 16 and/or Leu 19, but lacking expression of CD3. The rapid acquisition of cytotoxicity in the purified NK population implies that replication is not required for the generation of LAK activity. In conclusion, the potential for therapeutic application of IL-2 activated autologous lymphocytes has been clearly substantiated by clinical and experimental studies.