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James F. Miller, Ph.D.

James F. Miller, Ph.D.

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About Me

Professional Background

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 Depar...
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

Faculty Appointments

Professor (Part-Time) - Department of Microbiology and Immunology, Center for Vaccine Biology and Immunology (SMD)

Credentials

Post-doctoral Training & Residency

Postdoctoral Fellowship (Dr. Ronald N. Germain)
Laboratory of Immunology, NIAID, NIH 1983 - 1987

Education

PhD | Univ of Washington. Microbiology. 1983

MS | Univ of Washington. Microbiology. 1979

BA | Ithaca College. Biology. 1977

Research

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 t...
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.

Publications

Journal Articles

T cells Use Focal Adhesions to Pull Themselves Through Confined Environments.

Caillier A, Oleksyn D, Fowell DJ, Miller J, Oakes PW

bioRxiv : the preprint server for biology.. 2023 October 19 Epub 10/19/2023.

The CD28 Transmembrane Domain Contains an Essential Dimerization Motif.

Leddon SA, Fettis MM, Abramo K, Kelly R, Oleksyn D, Miller J

Frontiers in immunology.. 2020 11 :1519. Epub 07/16/2020.

Programming of Distinct Chemokine-Dependent and -Independent Search Strategies for Th1 and Th2 Cells Optimizes Function at Inflamed Sites.

Gaylo-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

Immunity.. 2019 August 2051 (2):298-309.e6. Epub 08/06/2019.

Pivotal role for ? integrins in sustained Tfh support of the germinal center response for long-lived plasma cell generation.

Schrock DC, Leddon SA, Hughson A, Miller J, Lacy-Hulbert A, Fowell DJ

Proceedings of the National Academy of Sciences of the United States of America.. 2019 February 15 Epub 02/15/2019.

Robust blind spectral unmixing for fluorescence microscopy using unsupervised learning.

McRae TD, Oleksyn D, Miller J, Gao YR

PloS one.. 2019 14 (12):e0225410. Epub 12/02/2019.

CD4 T Cell Epitope Specificity and Cytokine Potential Are Preserved as Cells Transition from the Lung Vasculature to Lung Tissue following Influenza Virus Infection.

DiPiazza A, Laniewski N, Rattan A, Topham DJ, Miller J, Sant AJ

Journal of virology.. 2018 July 192 (13)Epub 06/13/2018.

The Integrin LFA-1 Controls T Follicular Helper Cell Generation and Maintenance.

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

Immunity.. 2016 October 1845 (4):831-846. Epub 1900 01 01.

Regulatory T Cell Numbers in Inflamed Skin Are Controlled by Local Inflammatory Cues That Upregulate CD25 and Facilitate Antigen-Driven Local Proliferation.

Billroth-MacLurg AC, Ford J, Rosenberg A, Miller J, Fowell DJ

The Journal of immunology : official journal of the American Association of Immunologists.. 2016 September 15197 (6):2208-18. Epub 08/10/2016.

T cell receptor signaling can directly enhance the avidity of CD28 ligand binding.

Sanchez-Lockhart M, Rojas AV, Fettis MM, Bauserman R, Higa TR, Miao H, Waugh RE, Miller J

PloS one.. 2014 9 (2):e89263. Epub 02/24/2014.

Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: durable chimerism predicts outcome.

Leventhal J, Abecassis M, Miller J, Gallon L, Tollerud D, Elliott MJ, Bozulic LD, Houston C, Sustento-Reodica N, Ildstad ST

Transplantation.. 2013 January 1595 (1):169-76. Epub 1900 01 01.

The Spx regulator modulates stress responses and virulence in Enterococcus faecalis.

Kajfasz JK, Mendoza JE, Gaca AO, Miller JH, Koselny KA, Giambiagi-Demarval M, Wellington M, Abranches J, Lemos JA

Infection and immunity.. 2012 July 80 (7):2265-75. Epub 04/16/2012.

Favorable effects of alemtuzumab on allospecific regulatory T-cell generation.

Levitsky J, Leventhal JR, Miller J, Huang X, Chen L, Chandrasekaran D, Tambur AR, Mathew JM

Human immunology.. 2012 February 73 (2):141-9. Epub 11/23/2011.

Cutting edge: A role for inside-out signaling in TCR regulation of CD28 ligand binding.

Sanchez-Lockhart M, Kim M, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 2011 December 1187 (11):5515-9. Epub 11/07/2011.

The collagen-binding protein Cnm is required for Streptococcus mutans adherence to and intracellular invasion of human coronary artery endothelial cells.

Abranches J, Miller JH, Martinez AR, Simpson-Haidaris PJ, Burne RA, Lemos JA

Infection and immunity.. 2011 June 79 (6):2277-84. Epub 03/21/2011.

Requirement of cognate CD4+ T-cell recognition for the regulation of allospecific CTL by human CD4+ CD127- CD25+ FOXP3+ cells generated in MLR.

Yu Y, Miller J, Leventhal JR, Tambur AR, Chandrasekaran D, Levitsky J, Luo X, Mathew JM

PloS one.. 2011 6 (7):e22450. Epub 07/22/2011.

Common gamma chain cytokines promote rapid in vitro expansion of allo-specific human CD8+ suppressor T cells.

Yu Y, Zitzner JR, Houlihan J, Herrera N, Xu L, Miller J, Mathew JM, Tambur AR, Luo X

PloS one.. 2011 6 (12):e28948. Epub 12/14/2011.

TCR-dependent translational control of GATA-3 enhances Th2 differentiation.

Cook KD, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 2010 September 15185 (6):3209-16. Epub 08/09/2010.

Two pathways of costimulation through CD28.

Miller J, Baker C, Cook K, Graf B, Sanchez-Lockhart M, Sharp K, Wang X, Yang B, Yoshida T

Immunologic research.. 2009 December 45 (2-3):159-72. Epub 02/13/2009.

Signals and sequences that control CD28 localization to the central region of the immunological synapse.

Sanchez-Lockhart M, Graf B, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 2008 December 1181 (11):7639-48. Epub 1900 01 01.

LFA-1-mediated T cell costimulation through increased localization of TCR/class II complexes to the central supramolecular activation cluster and exclusion of CD45 from the immunological synapse.

Graf B, Bushnell T, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 2007 August 1179 (3):1616-24. Epub 1900 01 01.

Engagement of CD28 outside of the immunological synapse results in up-regulation of IL-2 mRNA stability but not IL-2 transcription.

Sanchez-Lockhart M, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 2006 April 15176 (8):4778-84. Epub 1900 01 01.

LFA-1 co-stimulation inhibits T(h)2 differentiation by down-modulating IL-4 responsiveness.

Jenks SA, Eisfelder BJ, Miller J

International immunology.. 2005 March 17 (3):315-23. Epub 02/07/2005.

Cutting edge: CD28-mediated transcriptional and posttranscriptional regulation of IL-2 expression are controlled through different signaling pathways.

Sanchez-Lockhart M, Marin E, Graf B, Abe R, Harada Y, Sedwick CE, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 2004 December 15173 (12):7120-4. Epub 1900 01 01.

Endoplasmic reticulum-associated degradation-induced dissociation of class II invariant chain complexes containing a glycosylation-deficient form of p41.

Sevilla LM, Comstock SS, Swier K, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 2004 August 15173 (4):2586-93. Epub 1900 01 01.

Molecular mechanisms of IL-2 gene regulation following costimulation through LFA-1.

Abraham C, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 2001 November 1167 (9):5193-201. Epub 1900 01 01.

Intracellular transport of MHC class II and associated invariant chain in antigen presenting cells from AP-3-deficient mocha mice.

Sevilla LM, Richter SS, Miller J

Cellular immunology.. 2001 June 15210 (2):143-53. Epub 1900 01 01.

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.

Jenks SA, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 2000 January 1164 (1):72-8. Epub 1900 01 01.

A role for the transmembrane domain in the trimerization of the MHC class II-associated invariant chain.

Ashman JB, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 1999 September 1163 (5):2704-12. Epub 1900 01 01.

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.

Abraham C, Griffith J, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 1999 April 15162 (8):4399-405. Epub 1900 01 01.

TCR, LFA-1, and CD28 play unique and complementary roles in signaling T cell cytoskeletal reorganization.

Sedwick CE, Morgan MM, Jusino L, Cannon JL, Miller J, Burkhardt JK

The Journal of immunology : official journal of the American Association of Immunologists.. 1999 February 1162 (3):1367-75. Epub 1900 01 01.

T cell recognition of flanking residues of murine invariant chain-derived CLIP peptide bound to MHC class II.

Naujokas MF, Southwood S, Mathies SJ, Appella E, Sette A, Miller J

Cellular immunology.. 1998 August 25188 (1):49-54. Epub 1900 01 01.

Functional consequences of costimulation by ICAM-1 on IL-2 gene expression and T cell activation.

Zuckerman LA, Pullen L, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 1998 April 1160 (7):3259-68. Epub 1900 01 01.

Endosomal proteases and antigen processing.

Fineschi B, Miller J

Trends in biochemical sciences.. 1997 October 22 (10):377-82. Epub 1900 01 01.

The proteolytic environment involved in MHC class II-restricted antigen presentation can be modulated by the p41 form of invariant chain.

Fineschi B, Sakaguchi K, Appella E, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 1996 October 15157 (8):3211-5. Epub 1900 01 01.

Proteolysis of major histocompatibility complex class II-associated invariant chain is regulated by the alternatively spliced gene product, p41.

Fineschi B, Arneson LS, Naujokas MF, Miller J

Proceedings of the National Academy of Sciences of the United States of America.. 1995 October 2492 (22):10257-61. Epub 1900 01 01.

Potent effects of low levels of MHC class II-associated invariant chain on CD4+ T cell development.

Naujokas MF, Arneson LS, Fineschi B, Peterson ME, Sitterding S, Hammond AT, Reilly C, Lo D, Miller J

Immunity.. 1995 September 3 (3):359-72. Epub 1900 01 01.

Invariant chain-independent antigen presentation depends primarily upon the pool of newly synthesized MHC class II molecules.

Swier K, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 1995 August 15155 (4):1851-61. Epub 1900 01 01.

Efficient internalization of MHC class II-invariant chain complexes is not sufficient for invariant chain proteolysis and class II antigen presentation.

Swier K, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 1995 July 15155 (2):630-43. Epub 1900 01 01.

Identification of a unique costimulatory activity for murine T helper 1 T cell clones.

Zuckerman LA, Sant AJ, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 1995 May 1154 (9):4503-12. Epub 1900 01 01.

Binding of major histocompatibility complex class II to the invariant chain-derived peptide, CLIP, is regulated by allelic polymorphism in class II.

Sette A, Southwood S, Miller J, Appella E

The Journal of experimental medicine.. 1995 February 1181 (2):677-83. Epub 1900 01 01.

MHC class II antigen processing: biology of invariant chain.

Sant AJ, Miller J

Current opinion in immunology.. 1994 February 6 (1):57-63. Epub 1900 01 01.

Endosomal localization of MHC class II-invariant chain complexes.

Miller J

Immunologic research.. 1994 13 (4):244-52. Epub 1900 01 01.

Expression and functional significance of an additional ligand for CTLA-4.

Lenschow DJ, Su GH, Zuckerman LA, Nabavi N, Jellis CL, Gray GS, Miller J, Bluestone JA

Proceedings of the National Academy of Sciences of the United States of America.. 1993 December 190 (23):11054-8. Epub 1900 01 01.

Enhanced antigen presentation in the absence of the invariant chain endosomal localization signal.

Anderson MS, Swier K, Arneson L, Miller J

The Journal of experimental medicine.. 1993 December 1178 (6):1959-69. Epub 1900 01 01.

The chondroitin sulfate form of invariant chain can enhance stimulation of T cell responses through interaction with CD44.

Naujokas MF, Morin M, Anderson MS, Peterson M, Miller J

Cell.. 1993 July 3074 (2):257-68. Epub 1900 01 01.

Anergized T cell clones retain their cytolytic ability.

Go C, Lancki DW, Fitch FW, Miller J

The Journal of immunology : official journal of the American Association of Immunologists.. 1993 January 15150 (2):367-76. Epub 1900 01 01.

The CD28 ligand, B7, enhances IL-2 production by providing a costimulatory signal to T cells.

Norton SD, Zuckerman L, Urdahl KB, Shefner R, Miller J, Jenkins MK

The Journal of immunology : official journal of the American Association of Immunologists.. 1992 September 1149 (5):1556-61. Epub 1900 01 01.

Antigen presentation enhanced by the alternatively spliced invariant chain gene product p41.

Peterson M, Miller J

Nature.. 1992 June 18357 (6379):596-8. Epub 1900 01 01.

Differential induction of transcription factors that regulate the interleukin 2 gene during anergy induction and restimulation.

Go C, Miller J

The Journal of experimental medicine.. 1992 May 1175 (5):1327-36. Epub 1900 01 01.

Invariant chain can function as a chaperone protein for class II major histocompatibility complex molecules.

Anderson MS, Miller J

Proceedings of the National Academy of Sciences of the United States of America.. 1992 March 1589 (6):2282-6. Epub 1900 01 01.

Invariant chain influences the immunological recognition of MHC class II molecules.

Peterson M, Miller J

Nature.. 1990 May 10345 (6271):172-4. Epub 1900 01 01.

Biosynthesis and intracellular transport of MHC class II molecules associated with a mutated, glycosaminoglycan-negative invariant chain.

Simonis S, Miller J, Cullen SE

Molecular immunology.. 1990 May 27 (5):413-22. Epub 1900 01 01.

Mechanism of action of cyclosporine A in vivo. II. T cell priming in vivo to alloantigen can be mediated by an IL-2-independent cyclosporine A-resistant pathway.

Pereira GM, Miller JF, Shevach EM

The Journal of immunology : official journal of the American Association of Immunologists.. 1990 March 15144 (6):2109-16. Epub 1900 01 01.

Accessory function of interleukin-1 and interleukin-6: preferential costimulation of T4 positive lymphocytes.

Tosato G, Miller J, Marti G, Pike SE

Blood.. 1990 February 1575 (4):922-30. Epub 1900 01 01.

Tissue-specific expression of allogeneic class II MHC molecules induces neither tissue rejection nor clonal inactivation of alloreactive T cells.

Miller J, Daitch L, Rath S, Selsing E

The Journal of immunology : official journal of the American Association of Immunologists.. 1990 January 1144 (1):334-41. Epub 1900 01 01.

The role of the Ia-invariant chain complex in the posttranslational processing and transport of Ia and invariant chain glycoproteins.

Simonis S, Miller J, Cullen SE

The Journal of immunology : official journal of the American Association of Immunologists.. 1989 December 1143 (11):3619-25. Epub 1900 01 01.

Diminished antigen processing by endosomal acidification mutant antigen-presenting cells.

McCoy KL, Miller J, Jenkins M, Ronchese F, Germain RN, Schwartz RH

The Journal of immunology : official journal of the American Association of Immunologists.. 1989 July 1143 (1):29-38. Epub 1900 01 01.

Physical linkage of mouse lambda genes by pulsed-field gel electrophoresis suggests that the rearrangement process favors proximate target sequences.

Storb U, Haasch D, Arp B, Sanchez P, Cazenave PA, Miller J

Molecular and cellular biology.. 1989 February 9 (2):711-8. Epub 1900 01 01.

The order and orientation of mouse lambda-genes explain lambda-rearrangement patterns.

Miller J, Ogden S, McMullen M, Andres H, Storb U

The Journal of immunology : official journal of the American Association of Immunologists.. 1988 October 1141 (7):2497-502. Epub 1900 01 01.

Identification of the glycosaminoglycan-attachment site of mouse invariant-chain proteoglycan core protein by site-directed mutagenesis.

Miller J, Hatch JA, Simonis S, Cullen SE

Proceedings of the National Academy of Sciences of the United States of America.. 1988 March 85 (5):1359-63. Epub 1900 01 01.

Specific antigen-Ia activation of transfected human T cells expressing murine Ti alpha beta-human T3 receptor complexes.

Saito T, Weiss A, Miller J, Norcross MA, Germain RN

Nature.. 1987 325 (7000):125-30. Epub 1900 01 01.

Efficient cell surface expression of class II MHC molecules in the absence of associated invariant chain.

Miller J, Germain RN

The Journal of experimental medicine.. 1986 November 1164 (5):1478-89. Epub 1900 01 01.

The murine interleukin-2 receptor: biochemical structure and regulation of expression.

Malek TR, Ashwell JD, Germain RN, Shevach EM, Miller J

Immunological reviews.. 1986 August 92 :81-101. Epub 1900 01 01.

Structure and function of murine class II major histocompatibility complex genes.

Germain RN, Braunstein NS, Brown MA, Glimcher LH, Lechler RI, McCluskey J, Margulies DH, Miller J, Norcross MA, Paul WE

The Mount Sinai journal of medicine, New York.. 1986 March 53 (3):194-201. Epub 1900 01 01.

Nucleotide sequence and expression of a mouse interleukin 2 receptor cDNA.

Miller J, Malek TR, Leonard WJ, Greene WC, Shevach EM, Germain RN

The Journal of immunology : official journal of the American Association of Immunologists.. 1985 June 134 (6):4212-7. Epub 1900 01 01.

Evolution of mouse immunoglobulin lambda genes.

Selsing E, Miller J, Wilson R, Storb U

Proceedings of the National Academy of Sciences of the United States of America.. 1982 August 79 (15):4681-5. Epub 1900 01 01.

Structural alterations in J regions of mouse immunoglobulin lambda genes are associated with differential gene expression.

Miller J, Selsing E, Storb U

Nature.. 1982 February 4295 (5848):428-30. Epub 1900 01 01.

Physical linkage of the constant region genes for immunoglobulins lambda I and lambda III.

Miller J, Bothwell A, Storb U

Proceedings of the National Academy of Sciences of the United States of America.. 1981 June 78 (6):3829-33. Epub 1900 01 01.

Rearrangement of immunoglobulin genes.

Wilson R, Miller J, Storb U

Biochemistry.. 1979 October 3018 (22):5013-21. Epub 1900 01 01.