Previous Academic Appointments
1987-1994 Assistant Professor, University of Chicago
1994-2002 Associate Professor with Tenure, University of Chicago
Department Molecular Genetics & Cell Biology
1988 Committee on Immunology
1989 Department of Pathology
1990 Committee on Developmental Biology
1994 Committee on Cancer Biology
1996 Committee on Cell Physiology
1999-2002 Chair, Committee on Immunology, University of Chicago
T cell activation requires the recognition of specific peptide-MHC complexes displayed on the surface of antigen presenting cells. T cell encounter with peptide-MHC ligands in the absence of an ongoing innate immune response generally does not lead to effective T cell activation and rather favors the induction of tolerance. One of the key consequences of the innate immune response is the upregulation of the ligands for CD28. Because CD28 is the major costimulatory molecule expressed on naïve T cells, CD28 can be viewed as the T cell-associated receptor for detection of the presence of a pathogen. This synergistic cross talk between TCR and CD28 provides a mechanism for coincidence detection to regulate T cell activation and control the initiation of T cell immune responses. One potential site of signal integration between the TCR and costimulatory signals is within the spatial organization of the immunological synapse. When T cells encounter an APC that expresses the appropriate peptide-MHC complex, the TCR is engaged, resulting in rapid upregulation of both the affinity and avidity of LFA-1 for its ligand, ICAM-1. This increased adhesion results in arrest of migration and a stable adhesion complex, or immunological synapse, is formed at the T cell:APC interaction site. Assembly of the immunological synapse provides for four important events: amplification of TCR signals on a limited number of peptide-MHC complexes, colocalization of TCR and costimulatory molecules and exclusion of phosphatases, providing for efficient signal integration, directional secretion of lytic granules, cytokines, and cell surface receptors toward the APC, and downregulation of TCR expression and signaling.
In this context we are interested in the following questions:
1. We have shown that the presence of LFA-1 is required for the exclusion of the cell surface phosphatase, CD45, from immunological synapse, induction of an initial calcium response, and sustained T cell:APC interactions. In the absence of LFA-1 T cells will become activated but it takes longer and the activated T cells will preferentially differentiate into Th2 cells. Our current studies are addressing how LFA-1 is regulated at the immunological synapse, how LFA-1 mediates CD45 exclusion, and how the duration of T cell:APC interactions impact on T cell activation and effector cell differentiation.
2. We have long standing interest in identifying the downstream signaling pathways initiated by CD28 costimulation and determining how these pathways are integrated with TCR signals to generate functionally different responses. Recently, we have initiated studies to determine how TCR signaling and ligand binding regulate CD28 triggering, resulting in localization of CD28 to the central region of the immunological synapse and initiation of downstream signaling events.
3. In addition to directional secretion, we have recently found that exocytosis of a subset of cytokines is signal dependent. We are now developing live cell imaging of T cell expressing cytokines fused to different fluorescent proteins to visualize Golgi sorting, vesicular transport, microtubule association, and plasma membrane fusion of vesicles containing cytokines that are regulated and/or directionally secreted.
4. Naïve CD4+ T cells differentiate into functionally distinct subsets that are central to both protection against pathogens and prevention of autoimmunity. GATA-3 is a developmentally regulated transcription factor that is necessary for Th2 differentiation. We have found that GATA-3 expression can be controlled at the translational level. Upregulation of both GATA-3 transcription and translation are required for Th2 differentiation. The model that we are currently testing is that signaling through PI3K and mTOR enhances the activity of the eIF4A RNA helicase, which is required for translation of mRNA with 5'UTR secondary structure.
2016 Oct 18
Meli AP, Fontés G, Avery DT, Leddon SA, Tam M, Elliot M, Ballesteros-Tato A, Miller J, Stevenson MM, Fowell DJ, Tangye SG, King IL. "The Integrin LFA-1 Controls T Follicular Helper Cell Generation and Maintenance." Immunity. 2016 Oct 18; 45(4):831-846.
2016 Sep 15
Billroth-MacLurg AC, Ford J, Rosenberg A, Miller J, Fowell DJ. "Regulatory T Cell Numbers in Inflamed Skin Are Controlled by Local Inflammatory Cues That Upregulate CD25 and Facilitate Antigen-Driven Local Proliferation." The Journal of immunology : official journal of the American Association of Immunologists. 2016 Sep 15; 197(6):2208-18. Epub 2016 Aug 10.
Sanchez-Lockhart M, Rojas AV, Fettis MM, Bauserman R, Higa TR, Miao H, Waugh RE, Miller J. "T cell receptor signaling can directly enhance the avidity of CD28 ligand binding." PloS one. 2014 9(2):e89263. Epub 2014 Feb 24.
2013 Jan 15
Leventhal J, Abecassis M, Miller J, Gallon L, Tollerud D, Elliott MJ, Bozulic LD, Houston C, Sustento-Reodica N, Ildstad ST. "Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: durable chimerism predicts outcome." Transplantation. 2013 Jan 15; 95(1):169-76.
Kajfasz JK, Mendoza JE, Gaca AO, Miller JH, Koselny KA, Giambiagi-Demarval M, Wellington M, Abranches J, Lemos JA. "The Spx regulator modulates stress responses and virulence in Enterococcus faecalis." Infection and immunity. 2012 Jul; 80(7):2265-75. Epub 2012 Apr 16.