James Miller
| Title | Professor |
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| Institution | School of Medicine and Dentistry |
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| Department | Microbiology and Immunology in the Center for Vaccine Biology and Immunology |
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| Address | University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 609
Rochester NY 14642
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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.
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Sanchez-Lockhart M, Kim M, Miller J. Cutting Edge: A Role for Inside-Out Signaling in TCR Regulation of CD28 Ligand Binding. J Immunol. 2011 Dec 1; 187(11):5515-9.
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Cook KD, Miller J. TCR-dependent translational control of GATA-3 enhances Th2 differentiation. J Immunol. 2010 Sep 15; 185(6):3209-16.
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Miller J, Baker C, Cook K, Graf B, Sanchez-Lockhart M, Sharp K, Wang X, Yang B, Yoshida T. Two pathways of costimulation through CD28. Immunol Res. 2009; 45(2-3):159-72.
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Sanchez-Lockhart M, Graf B, Miller J. Signals and sequences that control CD28 localization to the central region of the immunological synapse. J Immunol. 2008 Dec 1; 181(11):7639-48.
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Arneson LS, Miller J. The chondroitin sulfate form of invariant chain trimerizes with conventional invariant chain and these complexes are rapidly transported from the trans-Golgi network to the cell surface. Biochem J. 2007 Aug 15; 406(1):97-103.
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Graf B, Bushnell T, Miller J. 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. J Immunol. 2007 Aug 1; 179(3):1616-24.
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Sanchez-Lockhart M, Miller J. Engagement of CD28 outside of the immunological synapse results in up-regulation of IL-2 mRNA stability but not IL-2 transcription. J Immunol. 2006 Apr 15; 176(8):4778-84.
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Jenks SA, Eisfelder BJ, Miller J. LFA-1 co-stimulation inhibits T(h)2 differentiation by down-modulating IL-4 responsiveness. Int Immunol. 2005 Mar; 17(3):315-23.
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Sanchez-Lockhart M, Marin E, Graf B, Abe R, Harada Y, Sedwick CE, Miller J. Cutting edge: CD28-mediated transcriptional and posttranscriptional regulation of IL-2 expression are controlled through different signaling pathways. J Immunol. 2004 Dec 15; 173(12):7120-4.
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Sevilla LM, Comstock SS, Swier K, Miller J. Endoplasmic reticulum-associated degradation-induced dissociation of class II invariant chain complexes containing a glycosylation-deficient form of p41. J Immunol. 2004 Aug 15; 173(4):2586-93.
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Abraham C, Miller J. Molecular mechanisms of IL-2 gene regulation following costimulation through LFA-1. J Immunol. 2001 Nov 1; 167(9):5193-201.
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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. 2001 Jun 15; 210(2):143-53.
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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. 2000 Jan 1; 164(1):72-8.
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Ashman JB, Miller J. A role for the transmembrane domain in the trimerization of the MHC class II-associated invariant chain. J Immunol. 1999 Sep 1; 163(5):2704-12.
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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. 1999 Apr 15; 162(8):4399-405.
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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. 1999 Feb 1; 162(3):1367-75.
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Naujokas MF, Southwood S, Mathies SJ, Appella E, Sette A, Miller J. T cell recognition of flanking residues of murine invariant chain-derived CLIP peptide bound to MHC class II. Cell Immunol. 1998 Aug 25; 188(1):49-54.
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Zuckerman LA, Pullen L, Miller J. Functional consequences of costimulation by ICAM-1 on IL-2 gene expression and T cell activation. J Immunol. 1998 Apr 1; 160(7):3259-68.
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Fineschi B, Miller J. Endosomal proteases and antigen processing. Trends Biochem Sci. 1997 Oct; 22(10):377-82.
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Fineschi B, Sakaguchi K, Appella E, Miller J. The proteolytic environment involved in MHC class II-restricted antigen presentation can be modulated by the p41 form of invariant chain. J Immunol. 1996 Oct 15; 157(8):3211-5.
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Fineschi B, Arneson LS, Naujokas MF, Miller J. Proteolysis of major histocompatibility complex class II-associated invariant chain is regulated by the alternatively spliced gene product, p41. Proc Natl Acad Sci U S A. 1995 Oct 24; 92(22):10257-61.
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Naujokas MF, Arneson LS, Fineschi B, Peterson ME, Sitterding S, Hammond AT, Reilly C, Lo D, Miller J. Potent effects of low levels of MHC class II-associated invariant chain on CD4+ T cell development. Immunity. 1995 Sep; 3(3):359-72.
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Swier K, Miller J. Invariant chain-independent antigen presentation depends primarily upon the pool of newly synthesized MHC class II molecules. J Immunol. 1995 Aug 15; 155(4):1851-61.
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Swier K, Miller J. Efficient internalization of MHC class II-invariant chain complexes is not sufficient for invariant chain proteolysis and class II antigen presentation. J Immunol. 1995 Jul 15; 155(2):630-43.
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Arneson LS, Miller J. Efficient endosomal localization of major histocompatibility complex class II-invariant chain complexes requires multimerization of the invariant chain targeting sequence. J Cell Biol. 1995 Jun; 129(5):1217-28.
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Zuckerman LA, Sant AJ, Miller J. Identification of a unique costimulatory activity for murine T helper 1 T cell clones. J Immunol. 1995 May 1; 154(9):4503-12.
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Sette A, Southwood S, Miller J, Appella E. Binding of major histocompatibility complex class II to the invariant chain-derived peptide, CLIP, is regulated by allelic polymorphism in class II. J Exp Med. 1995 Feb 1; 181(2):677-83.
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Sant AJ, Miller J. MHC class II antigen processing: biology of invariant chain. Curr Opin Immunol. 1994 Feb; 6(1):57-63.
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Miller J. Endosomal localization of MHC class II-invariant chain complexes. Immunol Res. 1994; 13(4):244-52.
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Anderson MS, Swier K, Arneson L, Miller J. Enhanced antigen presentation in the absence of the invariant chain endosomal localization signal. J Exp Med. 1993 Dec 1; 178(6):1959-69.
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Lenschow DJ, Su GH, Zuckerman LA, Nabavi N, Jellis CL, Gray GS, Miller J, Bluestone JA. Expression and functional significance of an additional ligand for CTLA-4. Proc Natl Acad Sci U S A. 1993 Dec 1; 90(23):11054-8.
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Naujokas MF, Morin M, Anderson MS, Peterson M, Miller J. The chondroitin sulfate form of invariant chain can enhance stimulation of T cell responses through interaction with CD44. Cell. 1993 Jul 30; 74(2):257-68.
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Go C, Lancki DW, Fitch FW, Miller J. Anergized T cell clones retain their cytolytic ability. J Immunol. 1993 Jan 15; 150(2):367-76.
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Norton SD, Zuckerman L, Urdahl KB, Shefner R, Miller J, Jenkins MK. The CD28 ligand, B7, enhances IL-2 production by providing a costimulatory signal to T cells. J Immunol. 1992 Sep 1; 149(5):1556-61.
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Peterson M, Miller J. Antigen presentation enhanced by the alternatively spliced invariant chain gene product p41. Nature. 1992 Jun 18; 357(6379):596-8.
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Go C, Miller J. Differential induction of transcription factors that regulate the interleukin 2 gene during anergy induction and restimulation. J Exp Med. 1992 May 1; 175(5):1327-36.
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Anderson MS, Miller J. Invariant chain can function as a chaperone protein for class II major histocompatibility complex molecules. Proc Natl Acad Sci U S A. 1992 Mar 15; 89(6):2282-6.
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Peterson M, Miller J. Invariant chain influences the immunological recognition of MHC class II molecules. Nature. 1990 May 10; 345(6271):172-4.
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Simonis S, Miller J, Cullen SE. Biosynthesis and intracellular transport of MHC class II molecules associated with a mutated, glycosaminoglycan-negative invariant chain. Mol Immunol. 1990 May; 27(5):413-22.
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Pereira GM, Miller JF, Shevach EM. 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. J Immunol. 1990 Mar 15; 144(6):2109-16.
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Tosato G, Miller J, Marti G, Pike SE. Accessory function of interleukin-1 and interleukin-6: preferential costimulation of T4 positive lymphocytes. Blood. 1990 Feb 15; 75(4):922-30.
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Miller J, Daitch L, Rath S, Selsing E. Tissue-specific expression of allogeneic class II MHC molecules induces neither tissue rejection nor clonal inactivation of alloreactive T cells. J Immunol. 1990 Jan 1; 144(1):334-41.
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Simonis S, Miller J, Cullen SE. The role of the Ia-invariant chain complex in the posttranslational processing and transport of Ia and invariant chain glycoproteins. J Immunol. 1989 Dec 1; 143(11):3619-25.
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McCoy KL, Miller J, Jenkins M, Ronchese F, Germain RN, Schwartz RH. Diminished antigen processing by endosomal acidification mutant antigen-presenting cells. J Immunol. 1989 Jul 1; 143(1):29-38.
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Storb U, Haasch D, Arp B, Sanchez P, Cazenave PA, Miller J. Physical linkage of mouse lambda genes by pulsed-field gel electrophoresis suggests that the rearrangement process favors proximate target sequences. Mol Cell Biol. 1989 Feb; 9(2):711-8.
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Miller J, Ogden S, McMullen M, Andres H, Storb U. The order and orientation of mouse lambda-genes explain lambda-rearrangement patterns. J Immunol. 1988 Oct 1; 141(7):2497-502.
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Miller J, Hatch JA, Simonis S, Cullen SE. Identification of the glycosaminoglycan-attachment site of mouse invariant-chain proteoglycan core protein by site-directed mutagenesis. Proc Natl Acad Sci U S A. 1988 Mar; 85(5):1359-63.
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Saito T, Weiss A, Miller J, Norcross MA, Germain RN. Specific antigen-Ia activation of transfected human T cells expressing murine Ti alpha beta-human T3 receptor complexes. Nature. 1987 Jan 8-14; 325(7000):125-30.
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Miller J, Germain RN. Efficient cell surface expression of class II MHC molecules in the absence of associated invariant chain. J Exp Med. 1986 Nov 1; 164(5):1478-89.
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Malek TR, Ashwell JD, Germain RN, Shevach EM, Miller J. The murine interleukin-2 receptor: biochemical structure and regulation of expression. Immunol Rev. 1986 Aug; 92:81-101.
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Germain RN, Braunstein NS, Brown MA, Glimcher LH, Lechler RI, McCluskey J, Margulies DH, Miller J, Norcross MA, Paul WE, et al. Structure and function of murine class II major histocompatibility complex genes. Mt Sinai J Med. 1986 Mar; 53(3):194-201.
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Miller J, Malek TR, Leonard WJ, Greene WC, Shevach EM, Germain RN. Nucleotide sequence and expression of a mouse interleukin 2 receptor cDNA. J Immunol. 1985 Jun; 134(6):4212-7.
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Selsing E, Miller J, Wilson R, Storb U. Evolution of mouse immunoglobulin lambda genes. Proc Natl Acad Sci U S A. 1982 Aug; 79(15):4681-5.
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Miller J, Selsing E, Storb U. Structural alterations in J regions of mouse immunoglobulin lambda genes are associated with differential gene expression. Nature. 1982 Feb 4; 295(5848):428-30.
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Miller J, Bothwell A, Storb U. Physical linkage of the constant region genes for immunoglobulins lambda I and lambda III. Proc Natl Acad Sci U S A. 1981 Jun; 78(6):3829-33.
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Wilson R, Miller J, Storb U. Rearrangement of immunoglobulin genes. Biochemistry. 1979 Oct 30; 18(22):5013-21.
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