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FRISC: The Faculty Research Interests Science Comparator |
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Assistant Professor, Center for Immunology
Immunology
Office: (214) 648-7315
Lab: 214-648-7316
Fax: 214-648-7331
Email: david.farrar@utsouthwestern.edu
T cell ontogeny and development involves a series of lineage commitment
choices that are initiated from the earliest lymphoid progenitor cells and
continue to the final stages of terminal T cell differentiation during an immune
response. Regarding this process, the main focus of our lab is to define the
molecular processes involved in controlling terminal differentiation of naive
CD4+ T cells into functional subsets that secrete unique patterns of cytokines
termed T helper 1 (Th1) and Th2 cells. Th1 cells preferentially secrete IFN-@,
whereas Th2 cells secrete IL-4 and mediate cellular and humoral responses,
respectively. Further, cytokines themselves, produced by innate immune cells
(macrophages and dendritic cells), are critical components to this developmental
process. My current research has involved the functional characterization of the
type I interferon (IFN-@/@) receptor and the influence of type I interferons on
peripheral CD4+ T helper cell development. Signals delivered through the IFN-@/@
receptor (IFNAR) induce a variety of innate antiviral responses, which occur in
virtually all somatic cells. Additionally, there are responses to IFN-@/@ that
are unique to specific cell types, and specifically, CD4+ T cells. Importantly,
type I interferons exert therapeutic effects in humans that are not completely
understood in terms of mechanism, making animal models of importance in
directing further clinical efforts. However, our work has uncovered a completely
unanticipated difference in IFN-@/@ signaling between mice and humans that
explains how IFN-@/@ induces Th1 development in human, but not mouse, CD4+ T
cells.
By characterizing the signaling pathway of the human IFNAR, I discovered a
remarkable mechanistic difference that accounts for IFN-@/@-induced Th1
development in human, but not murine CD4+ T cells. In human T cells, IFN-@/@
signaling activates an important transcription factor, Signal Transducer and
Activator of Transcription (Stat)4, but such activation does not occur in murine
CD4+ T cells in response to IFN-@/@. Human Stat2 acts as an adaptor molecule to
recruit Stat4 to the human IFNAR, but this molecular bridge does not exist in
the mouse because there is a high degree of sequence divergence in the region of
Stat2 responsible for docking of Stat4. Thus, the mouse has a specific defect
blocking the ability of CD4+ T cells to activate Stat4 and undergo Th1
development in response to IFN-@/@. Further, with regard to Th1 development,
this specific link between innate and adaptive immunity in humans, bridged by
type I interferons, does not exist in mice.
Some important questions related to these observations will be addressed:
1. What are the consequences for humans resulting from type I IFN-induced Th1
development? Are there specific advantages afforded to humans by this pathway
during interactions with pathogens that elicit type I IFN responses?
2. What is the structural basis for latent versus activated Stat2/Stat4
interactions? What is the molecular mechanism by which a single SH2-domain
containing molecule (Stat4) requires interactions with 2 tyrosine residues
within Stat2?
3. How do signals delivered by the hIFNAR (constitutively expressed on all
cells) impact other cross-regulatory signals such as those mediated by the
IL-4R? Does simultaneous signaling by IFN-@/@ and IL-4 account for the
observation that human CD4+ T cells have a greater propensity for expressing
both IFN-@ and IL-4 under some circumstances?
4. Are there unique human Stat2-interacting molecules and human IFN-@/@
responsive genes that would not be revealed in the murine system, and how would
these genes participate in human Th differentiation?
Selected Publications:
Farrar, J.D., Asnagli, H., Murphy, K.M. (2001). Instructive versus selective
mechanisms regulating CD4+ T helper cell differentiation. J. Clin. Invest.,
submitted.
Farrar, J.D., Murphy, K.M. (2001). Cytokines and Type I Immunity. in Samter's
Immunologic Diseases, Sixth Edition, Ed; Austin KF, Frank MM, Atkinson JP,
Cantor H; Pub; Lippincott Williams & Wilkins, Baltimore, MD., in press.
Farrar, J.D., Ouyang, W., Lohning, M., Assenmacher, M., Radbruch, A.,
Kanagawa, O., Murphy, K.M. (2001). An instructive component in T helper cell
type 2 (Th2) development mediated by GATA-3. J. Exp. Med., 193, 643-649.
Farrar, J.D., Murphy, K.M. (2000). Type I interferon and T helper
development. Immunol. Today, 21, 484-489.
Murphy, T.L., Geissal, E.D., Farrar, J.D., Murphy, K.M. (2000). Role of the
Stat4 N-domain in receptor proximal tyrosine phosphorylation. Mol. Cell.
Biol., 20, 7121-7131.
Farrar, J.D., Smith, J.D., Murphy, T.L., Leung, S., Stark, G.R., Murphy, K.M.
(2000). Selective loss of Type I interfon-induced Stat4 activation caused by a
minisatellite insertion in mouse Stat2. Nature Immunology, 1, 65-69.
Murphy, K.M., Ouyang, W., Farrar, J.D., Yang, J., Ranganath, S., Asnagli, H.,
Afkarian, M., Murphy, T.L. (2000). Signaling and transcription in T helper
development. Annu. Rev. Immunol., 18, 451-494.
Farrar, J.D., Smith, J.D., Murphy, T.L., Murphy, K.M. (2000). Recruitment of
Stat4 to the human IFN-a/b receptor requires activated Stat2. J. Biol. Chem.,
275, 2693-2697.
Farrar, J.D., Ranganath, S.H., Murphy, K.M. Molecular mechanisms in T helper
phenotype development. (1999). Springer Seminars in Immunopathology,
21(3), 211-230.
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