Primary Academic Appointment:
  Dept. of Microbiology and Immunology

Center Affiliation:
  Center for Vaccine Biology and Immunology

GEBS Cluster Affiliations:
 Immunology, Microbiology, and Virology - IMV

University of Rochester
School of Medicine and Dentistry
601 Elmwood Ave, Box 609
Rochester, New York 14642

Phone: (585) 275-9698
E-Mail: jim_miller@urmc.rochester.edu

Role of LFA-1 in T Cell Costimulation

The primary focus of my research is to unravel basic cellular and molecular mechanisms that underlie T cell recognition of antigen. T cell activation is associated with a dramatic reorganization of cell surface receptors, cytosolic signaling molecules, and cytoskeletal elements within the adhesion complex that forms between a T cell and antigen presenting cell. This has been termed the immunological synapse.

We have found that the selective engagement of adhesion and costimulatory molecules can differentially regulate the organization of proteins within the immunological synapse; this can lead to further changes in gene expression. We are currently using in vitro mutagenesis, recombinant fusion proteins, and retroviral gene transfer combined with biochemical and microscopic analysis, including live cell imaging, to identify the factors and interactions that determine the specific localization of proteins within the immunological synapse and how this localization impacts on signal integration and regulation of gene expression.

In addition, we have found costimulation through the integrin LFA-1 can inhibit the generation of Th2 effector T cells. We are currently evaluating the biochemical and molecular events that control this cell lineage commitment event and how these events are regulated by LFA-1 and other costimulatory molecules.

Jenks, S. A. Eisfelder, B. J. Miller, J. "LFA-1 co-stimulation inhibits T(h)2 differentiation by down-modulating IL-4 responsiveness." Int Immunol 17(3): 315-23, 2005.

Sanchez-Lockhart M, Marin E, Graf B, Abe R,  Harada Y, Sedwick C. E, Miller, J. "Cutting edge: CD28-mediated transcriptional and posttranscriptional regulation of IL-2 expression are controlled through different signaling pathways." J Immunol 173(12): 7120-4, 2004.

Abraham C, Miller J. Molecular mechanisms of IL-2 gene regulation following costimulation through LFA-1. J Immunol. 167:5193-201, 2001.

Sevilla LM, Richter SS, Miller J. Intracellular transport of MHC class II and associated invariant chain in antigen presenting cells from AP-3-deficient mocha mice. Cell Immunol. 210:143-53, 2001.

Jenks SA, Miller J. Inhibition of IL-4 responses after T cell priming in the context of LFA-1 costimulation is not reversed by restimulation in the presence of CD28 costimulation. J Immunol. 164:72-8, 2000.

Ashman JB, Miller J. A role for the transmembrane domain in the trimerization of the MHC class II-associated invariant chain. J Immunol. 163:2704-12, 1999.

Abraham C, Griffith J, Miller J. The dependence for leukocyte function-associated antigen-1/ICAM-1 interactions in T cell activation cannot be overcome by expression of high density TCR ligand. J Immunol. 162:4399-405, 1999.

Sedwick CE, Morgan MM, Jusino L, Cannon JL, Miller J, Burkhardt JK. TCR, LFA-1, and CD28 play unique and complementary roles in signaling T cell cytoskeletal reorganization. J Immunol. 162:1367-75, 1999.