Kenneth M. Murphy, M.D., Ph.D.

DEPARTMENT OF Pathology & Immunology
Keywords: lymphocyte, differentiation, gene expression, transcription, inflammation

The major theme of my laboratory is the study of lineage commitment programs. The majority of our work has focused on lineage choices within the immune system, with special interest in T cell development. In addition, our laboratory is interested in early fate choices during embryonic development, such as the mechanisms that generate mesoderm, from which the entire immune system is derived.

The immune system makes many lineage choices. One important choice is made by CD4⁺ T cells, the cells destroyed by HIV in AIDS. Naïve CD4⁺ T cells choose between several lineages during an immune response to pathogens, generating different effector subsets. These include subsets named Th1, Th17, Th2 and various regulatory subsets. We pioneered the use of TCR-transgenic mouse to study such T cell differentiation in vitro. With this system, we defined important signals that direct these choices, such as the cytokines IL-12 and IL-4 that act by the JAK/STAT pathway to initiate the Th1 or Th2 programs. We identified many transcriptional steps in Th1 and Th2 differentiation, such as STAT1 induction of T-bet, which induces expression of the IL-12 receptor, allowing for IL-12 activation of STAT4 and subsequent Th1 expansion and effector activity. Current projects in T cell development include analysis of several knockout mice for several new transcription factors that are expressed in a highly polarized manner in T cell subsets.

Work in this area led to the discovery of several novel molecules. We cloned the B and T lymphocyte attenuator (BTLA), a novel receptor expressed by T and B cells. We made BTLA knockout mice to study its role in the immune response, and found increased T cell responses, indicating an inhibitory role for BTLA, and have examined aspects of its signaling, which includes recruitment of inhibitory phosphatases such as SHP-2. Polymorphisms in human BTLA have now been associated with susceptibility to diseases such as Rheumatoid arthritis. A highly unexpected finding came from our search for the natural BTLA ligand. The BTLA ligand was not a member of the B7 immunoglobulin superfamily, as expected, but was a member of the TNF receptor superfamily, Herepesvirus entry mediator (HVEM). This finding represents the first example of an immunoglobulin (Ig) domain receptor interacting with a receptor from the TNFR family.

New projects include other lineage decisions. In the immune system, we study the development of myeloid cells into neutrophils, macrophages, and dendritic cells (DCs). We have identified several novel transcription factors that expressed in discrete myeloid subsets and are now examining their role in vivo using knockout mice. We are interested in the choice made by precursors that distinguishes macrophages from DCs in particular, since DCs are critical to directing the differentiation of CD4 T cells. Finally, a newer project uses embryonic stem (ES) cells to dissect the transcriptional basis of mesoderm development. Our early studies in this area identified the Wnt signaling pathway as critical for inducing the transcription factors that drive development of specific subsets of mesoderm, and we have identified several transcription factors that regulate the development of early mesoderm lineages, such as early components the cardiovascular system.