CONTACT INFORMATIONBIOGRAPHYCREDENTIALSPUBLICATIONSJames F. Miller, Ph.D.Contact InformationPhone NumbersAdministrative: (585) 273-1400Office: (585) 275-9698Fax: (585) 273-2452LocationsUniversity of Rochester Medical CenterSchool of Medicine and Dentistry601 Elmwood Ave, Box 609Rochester, NY 14642Additional LinksProgram for Advanced Immune BioimagingFaculty AppointmentsProfessor (Part-Time) - Department of Microbiology and Immunology , Center for Vaccine Biology and Immunology (SMD) BiographyT 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.Professional BackgroundPrevious 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 ChicagoResearchT 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.CredentialsEducation1977BA | Ithaca CollegeBiology1979MS | Univ of WashingtonMicrobiology1983PhD | Univ of WashingtonMicrobiologyPost-doctoral Training & Residency1983 - 1987Postdoctoral Fellowship (Dr. Ronald N. Germain) Laboratory of Immunology, NIAID, NIHPublicationsJournal Articles1/4/2022Richards KA, Lavery C, Keller GLJ, Miller J, Baker BM, Sant AJ. "A previously unappreciated polymorphism in the beta chain of I-A expressed in autoimmunity-prone SJL mice: Combined impact on antibody, CD4 T cell recognition and MHC class II dimer structural stability." Molecular immunology.. 2022 Jan 4; 143:17-26. Epub 2022 Jan 04. 2020Leddon SA, Fettis MM, Abramo K, Kelly R, Oleksyn D, Miller J. "The CD28 Transmembrane Domain Contains an Essential Dimerization Motif." Frontiers in immunology.. 2020 11:1519. Epub 2020 Jul 16. 8/20/2019Gaylo-Moynihan A, Prizant H, Popovic M, Fernandes NRJ, Anderson CS, Chiou KK, Bell H, Schrock DC, Schumacher J, Capece T, Walling BL, Topham DJ, Miller J, Smrcka AV, Kim M, Hughson A, Fowell DJ. "Programming of Distinct Chemokine-Dependent and -Independent Search Strategies for Th1 and Th2 Cells Optimizes Function at Inflamed Sites." Immunity.. 2019 Aug 20; 51(2):298-309.e6. Epub 2019 Aug 06. VIEW ALL PUBLICATIONSClose WindowSchedule an appointment with James F. Miller, Ph.D.Please answer the following questions to help us find the right appointment for you.Important: If you believe that you have a medical or psychiatric emergency, please call 911 or go to the nearest hospital. This website is not intended for emergency care.Have you seen this provider in the last 2 years?YesNoExisting Patient Schedule or request a follow up appointment online through MyChart. 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