Richard Locksley, MD

Investigator, Howard Hughes Medical Institute
Professor
Department of Medicine - Infectious Disease
locksley@medicine.ucsf.edu

Vertebrate immunity is organized into modules such that stereotyped patterns of cytokines – the immune ‘language’ – are used during responses to different types of organisms.  For rapidly replicating pathogens, like most bacteria, viruses and fungi, inflammatory cytokines mediate the recruitment and activation of cells to enhanced microbicidal states (represented by ‘activated macrophages’, for instance) that are necessary to kill organisms and limit infection.  Although these inflammatory responses can lead to pathology, such as seen in septic shock, regulatory processes are also invoked that control the immune attack and re-establish homeostasis through mechanisms that additionally lead to the establishment of protective memory T cells and antibody-producing B cells and plasma cells.  The evolutionary importance of these immune responses is illuminated by the consequences of human mutations in these pathways that lead to an inability to contain infectious organisms.

While these protective responses are fairly well understood, the immune response typified as ‘allergy’ remains more puzzling.  Allergic inflammation is characterized by the infiltration of tissues by eosinophils and basophils, which are rare myeloid cells that comprise only a few percent of circulating blood cells.  The adaptive allergic response is characterized by increases in the numbers of Th2 cells that release interleukin-4 (IL-4), IL-5 and IL-13 and the development of plasma cells that secrete immunoglobulin E (IgE).  When sustained, these responses can lead to alterations at mucosal epithelial surfaces, including increases in the number of mucus-secreting cells and increased deposition of collagen in the tissues.  These responses can be protective in healing the epithelium from chronic attack by parasitic worms, such as hookworms and schistosomes.  When this type of immunity becomes focused on common environmental exposures, however, such as inhaled dust mites or mold or consumed shellfish, the result can be allergies, including potentially life-threatening afflictions such as asthma and food allergy, which affect, respectively, more than 20 million and 2 million Americans.

Our laboratory defined an environmental trigger, chitin, which is a polysaccharide required for structural integrity in insects, fungi and helminthes, as a potent stimulus for activation of innate cytokines associated with allergic, or type 2, immunity.  Further investigation revealed that the target of chitin was rare innate lymphoid cells, now termed Group 2 innate lymphoid cells, or ILC2s, that constitute the major innate source of IL-13 and IL-5, key cytokines that comprise the ‘language’ of allergy.  These cells are dispersed throughout tissues during fetal development and, when activated, result in a stereotyped cytokine response that results in accumulation of eosinophils and ‘alternatively activated’ macrophages in affected tissues.  With continued stimulation, adaptive responses characterized by recruitment of Th2 cells and production of IgE occurs, thus exposing a fundamental pathway central to allergic immunity.

One of our major focuses remain the endogenous upstream signals that activate ILC2s and the downstream signals by which the tissues respond to re-establish homeostasis.  When administered to animals, chitin induces focal areas of mucosal injury, leading to the production of epithelial cytokines TSLP, IL-33 and IL-25.  ILC2s constitutively express receptors for these cytokines, and respond by secreting cytokines and growth factors.  In the absence of these epithelial cytokines, ILC2 cytokines are not released, and, when ILC2s are deleted, the infiltration of inflammatory cells and the extent of tissue injury are increased.  A major target of IL-13 derived from activated ILC2s is induction of epithelial mucins and chitinase enzymes that clear and degrade the insoluble polysaccharide, thus re-establishing airway homeostasis.  A major target of IL-5 is the accumulation of tissue eosinophils, although their precise role remains undefined.  We continue efforts to understand the role of these epithelial processes in maintaining lung homeostasis against environmental challenges and have begun to extend these findings to human lung diseases characterized by inflammation, tissue injury and subepithelial fibrosis, such as asthma, to understand how they become dysregulated.

Despite elevated Th2 cells, eosinophils and IgE, human intestinal helminth infections are not cleared over many years, suggesting that helminthes may exploit these pathways for their own survival.  In an effort to define physiologic roles for eosinophils, we noted that these rare cells reside constitutively in visceral adipose and small intestine lamina propria.  We confirmed that alternatively activated macrophages were also localized to these sites, suggesting that local ILC2 activation might explain the residence of these innate cells otherwise associated with allergy.  We showed that eosinophils were necessary to sustain normal cellular homeostasis in adipose tissues and that eosinophil-deficient mice were unable to control metabolic responses when placed on a high-fat diet.  Unexpectedly, the presence of eosinophils was due to ILC2s in adipose, where these cells constitutively secreted cytokines required for eosinophil recruitment and for the alternative activation of macrophages.  Indeed, using novel mice with activation-induced deletion of ILC2s, we demonstrated that serum IL-5 necessary for basal bone marrow eosinophilopoiesis is derived from tissue ILC2s, and that ILC2s constitutively express receptors for intestinal neuropeptides that activate these cells in response to food intake.  These studies have uncovered basal physiologic conditions regulated by these rare ‘allergic’ cells, and have opened new avenues of investigation into potential roles for these cells in vertebrate biology in metabolism, wound healing and adaptive thermogenesis.

Primary Thematic Area: 
Immunology
Secondary Thematic Area: 
Virology & Microbial Pathogenesis
Research Summary: 
The Locksley lab is studying the foundations of allergic immunity and attempting to define the underlying processes mediated by this type of host response

Websites

Publications: 

Turning the light on.

Nature reviews. Immunology

Locksley R

The Development of Steady-State Activation Hubs between Adult LTi ILC3s and Primed Macrophages in Small Intestine.

Journal of immunology (Baltimore, Md. : 1950)

Savage AK, Liang HE, Locksley RM

Recruited Monocytes and Type 2 Immunity Promote Lung Regeneration following Pneumonectomy.

Cell stem cell

Lechner AJ, Driver IH, Lee J, Conroy CM, Nagle A, Locksley RM, Rock JR

Spontaneous Chitin Accumulation in Airways and Age-Related Fibrotic Lung Disease.

Cell

Van Dyken SJ, Liang HE, Naikawadi RP, Woodruff PG, Wolters PJ, Erle DJ, Locksley RM

Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s.

The Journal of experimental medicine

von Moltke J, O'Leary CE, Barrett NA, Kanaoka Y, Austen KF, Locksley RM