Eric O. Long, Ph.D.

Chief, Molecular and Cellular Immunology Section

Dr. Long received his Ph.D. from the University of Geneva, Switzerland, in 1976. After a postdoctoral fellowship at the National Cancer Institute from 1977 to 1980, Dr. Long joined the faculty of the University of Geneva as a junior member. In 1983, he was recruited to NIH as a tenure-track investigator in the Laboratory of Immunogenetics. He became section head in 1988 and was elected to the Senior Biomedical Research Service in 1998. Dr. Long is a recipient of the NIH Director's Award and is a member of the advisory board for the International Histocompatibility Working Group.

Description of Research Program

Natural killer (NK) cells provide a link between the innate and adaptive immune systems by responding rapidly to a variety of intracellular pathogens. In response to cytokines produced after infections, NK cells secrete other cytokines that regulate T-cell responses. In addition, NK cells kill infected target cells and tumor cells. Selective killing results from a balance between inhibitory NK receptors specific for MHC class I and a large number of activating receptors. The NK inhibitory receptors fulfill their function by recruiting the tyrosine phosphatase SHP-1 through a cytoplasmic immunoreceptor tyrosine-based inhibition motif (ITIM). The ITIM has become the hallmark of a growing number of receptors with inhibitory potential that are expressed in various cell types such as lymphocytes, monocytes, macrophages, and dendritic cells.

The main goal of the Molecular and Cellular Immunology Section (MCIS) is to understand how target cell killing by NK cells is regulated by multiple receptor-ligand interactions. Our recent work has shown that inhibitory receptors block NK cytotoxicity by de-phosphorylation of Vav1, a central regulator of actin polymerization. As signaling through activation receptors is downstream of actin cytoskeleton reorganization, an early block of actin polymerization can explain the inhibitory effect. The contribution of individual activation receptors to target cell killing is being dissected using an insect cell line as a surrogate target cell, into which ligands of NK receptors are expressed by transfection. This approach has revealed that the adhesion receptor LFA-1 is sufficient to trigger NK cytotoxicity.

Current specific aims are to: 1) test if Vav1 dephosphorylation is sufficient to block NK cytotoxicity; 2) study how inhibitory receptors become phosphorylated upon binding to MHC class I; 3) define how LFA-1 signals for cytotoxicity; 4) determine the role of other activation receptors; and 5) use confocal microscopy to study signals that regulate the NK immune synapse.

The Tyrosine Phosphatase SHP-l is Required for the Inhibitory Signal Delivered by the KIR

Memberships

• American Association of Immunologists
• Advisory/Review Board: American Association of
  Immunologists Program Committee

Research Group Members

Left to right, front row: Béatrice Riteau, Chris Stebbins, Priya Kuppusamy.
Back row: Eric Long, Nicolas Schleinitz, Mike March, Mary Peterson, Yenan Bryceson, Sumi Rajagopalan.
Not Pictured: Asmita Das, Christine Winter.

Selected Publications

(Search PubMed.)

Long EO. Regulation of immune responses through inhibitory receptors. Ann Rev Immunol. 1999. 17: 875-904.

Rajagopalan S, Fu J, Long EO. Cutting Edge: Induction of IFN-gamma production but not cytotoxicity by the killer cell lg-like receptor KIR2DL4 (CD158d ) in resting NK cells. J Immunol. 2001. 167: 1877-1881.

Watzl C, Long EO. Natural killer cell inhibitory receptors block actin cytoskeleton-dependent recruitment of 2B4 (CD244) to lipid rafts. J Exp Med. 197: 77-85.

Stebbins CC, Watzl C, Billadeau DD, Leibson PJ, Burshtyn DN, Long EO. Vav1 dephosphorylation by the phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity. Mol Cell Biol. 23: 6291-6299.

Riteau B, Barber DF, Long EO. Vav1 phosphorylation is induced by Beta2 integrin engagement on NK cells upstream of actin cytoskeleton and lipid raft reorganization. J Exp Med. 198: 469-474.