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Lineage Commitment in Immunity

Research Summary

Ken Murphy's laboratory studies the development and function of various immune lineages that contribute to immune responses, particulary T cell–dependent immune responses to intracellular pathogens. His lab is currently interested in understanding the development of dendritic cells into the several specialized lineages that underlie divergent T cell differentiation in response to varied pathogens.

Our goal is to improve the ability of vaccines to induce T cell–dependent immune responses. The inability of synthetic vaccines to induce strong T cell immunity is a critical obstacle in treating HIV, tuberculosis, and cancers. We aim to uncover the physiological processes that drive T cell–dependent immunity.

We began by examining the basis for the differentiation of various effector T cell subsets, discovering the role of antigen-presenting cells in directing T cell differentiation, identifying cytokines (such as interleukin-12 [IL-12] and IL-4) that instruct differentiation, and elaborating signaling pathways and transcription factors (such as STAT4 and GATA3) that mediate these instructive cues. This work has led to an understanding of several important effector subsets that differentiate and coordinate innate defenses against a variety of pathogens. Despite the importance of these basic pathways, it has been difficult to apply this knowledge to improve a vaccine's ability to elicit strong and durable T cell immunity. Because of this, we have recently turned our attention to the driver of the response, the dendritic cell.

The biology of dendritic cells is currently at the frontier of immunology. These accessory cells, which are responsible for inducing T cell–dependent responses in vivo, comprise several distinct sublineages with nonredundant physiologic functions that rely on different transcriptional programs of development. Both the developmental pathways and the cellular mechanisms underlying the unique activities of dendritic cell subsets are presently unknown and a matter of active research. Our current aim is to delineate the molecular and cellular pathways for dendritic cell development, and to understand the basis for the specialization of dendritic cells into several functionally distinct sublineages. As part of this effort, we recently identified the transcription factor Zbtb46 as capable of identifying dendritic cells committed to classical, and not plasmacytoid, sublineages.

For defense against the most threatening human pathogens, including HIV, tuberculosis, and malaria, as well as for eliciting antitumor immune responses, it is critical to promote the expansion of T helper type 1 (Th1) CD4 that produce interferon-γ and to elicit strongly cytolytic CD8 T cell effector responses. For this to occur, a particular subset of dendritic cell, known as the CD8α+ classical dendritic cell, must participate in the initial activation of T cells. We recently identified the transcription factor Batf3, which is selectively responsible for the development of this subset of dendritic cells. Mice lacking this factor fail to generate CD8 T cell responses against many viruses that require cross-presentation for their initial recognition, and fail to generate the IL-12 necessary to resist infection by certain intracellular pathogens.

Batf3, and the related Batf and Batf2 members of the AP-1 family exert a distinct transcriptional specificity from canonical AP-1 factors such as the Fos/Jun heterodimer. We discovered that Batf exerts selective control over specific processes in several subsets of CD4 T cells differentiation, and that unrecognized compensation between Batf and Batf3 masks their role in control of even wider programs, including the regulation of IL-10, a critically important cytokine involved in controlling inflammation. We recently discovered the basis for this transcriptional specificity as being due to the ability of Batf factors to interact with members of the IRF family, in particular IRF4 and IRF8, through outward facing residues of the Batf leucine zipper domain.

While we continue to explore the actions of Batf factors in immune cell development, we also pursue a more general program to identify novel factors that control other stages of dendritic cell differentiation, including the basis for lineage and sublineage divergences. We are also analyzing the molecular and cellular basis for functional specialization of distinct types of dendritic cells, in particular, the basis for cross-presentation and selective cytokine production during infections. Basic information of this nature may be applicable to the design of strategies that will improve the capacity for synthetic

Grants from the National Institutes of Health, the Cancer Research Insitute, and the American Heart Association have provided support to trainees and the lab.

As of March 24, 2016

Scientist Profile

Investigator
Washington University in St. Louis
Immunology, Medicine and Translational Research