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Faculty > Faculty By Research Interest > Janet Connolly, PhD

Professor, Pathology and Immunology
Professor, Genetics
Room 8849A, CSRB
Office: (314) 362-3958
Lab: (314) 362-2869
E-mail: connolly@wustl.edu
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Research

Research in my lab focuses on the development and function of CD8 T lymphocytes, which provide a major host defense against intracellular pathogens and tumors. Major histocompatibility complex class I molecules (MHCI) bind intracellular peptides derived from self or foreign proteins (viral or tumor) and display peptide/MHCI complexes on the cell surface for recognition by CD8 T cells. To create a more immunogenic peptide/MHCI complex that is also resistant to immune evasion mechanisms we have developed a strategy to express MHCI molecules as single chain trimers (SCT) consisting of antigenic peptide, B2m, and heavy chain covalently attached with flexible linkers. These SCT are potent simulators of peptide-specific cytotoxic CD8 T cells and antibodies specific for peptide/MHCI. We are currently testing these SCT for their potential as DNA vaccines against viruses and tumors.

We are also interested in how CD8 T cells react with exquisite specificity against foreign antigens while maintaining tolerance to self. Therefore, we have also engineered transgenic mice that express a single SCT complex to the exclusion of all other MHCI molecules. We are using these mice to define how the development of CD8 T cells is influenced by the expression of a single peptide/MHCI complex. We will determine how selection on a single peptide/MHCI complex influences the size and diversity of the CD8 T cell repertoire. We will also establish the relationship between the selecting and cognate peptides and determine the impact of structural similarity of the peptides on the development and function of the CD8 T cell repertoire.

Editorial Responsibilities

1998 - 2002Section EditorJournal of Immunology
1994 - 1998Associate EditorJournal of Immunology

Service to the University

2003 - PresentW. M. Keck Postdoctoral Fellowship Committee
1997 - PresentGraduate Admissions Committee, Immunology Program
1997 - 2001Disclosure Review Committee

DBBS Graduate Program Affiliation

Immunology Program
Molecular Genetics Program

Selected Publications

Wang B, Primeau TM, Myers N, Rohrs HW, Gross ML, Lybarger L, HansenTH, Connolly JM. A single peptide-MHC complex positively selects a diverse and specific CD8 T cell repertoire. Science 326:871-874, 2009 Abstract
Science Abstract
Full Text

Truscott SM, Lybarger L, Martinko JM, Mitaksov VE, Kranz DM, Connolly JM, Fremont DH, Hansen TH.. Disulfide bond engineering to trap peptides in the MHC class I binding groove.. J Immunol 178:6280-6289, 2007 Abstract

Purtha WE, Myers N, Mitaksov V, Sitati E, Connolly JM, Fremont DH, Hansen TH, Diamond MS.. Antigen-specific cytotoxic T lymphocytes protect against lethal West Nile Virus encephalitis.. European J Immunol 37:1845-1854, 2007 Abstract

Mitaksov V, Truscott SM, Lybarger L, Connolly JM, Hansen TH, Fremont DH.. Structural engineering of pMHC reagents for Tcell vaccines and diagnostics.. Chem & Biol, 2007 Abstract

Primeau T, Myers NB, Yu YY, Lybarger L, Wang X, Truscott SM, Hansen TH, Connolly JM.. Applications of MHC class I molecules expressed as single chains.. Immunol Res 32:109-122, 2005 Abstract

Hornell TM, Myers N, Hansen TH, Connolly JM.. Homology between an alloantigen and a self-allele calibrates the avidity of the alloreactive T cell repertoire independent of TCR affinity.. J Immunol 170:4506-4514, 2003 Abstract

Lybarger L, Yu YY, Miley MJ, Fremont DH, Myers N, Primeau T, Truscott SM, Connolly JM, Hansen TH.. Enhanced immune presentation of a single-chain major histocompatibility class I molecule engineered to optimize linkage of C-terminal extended peptide.. J Biol Chem 278:27105-27111, 2003 Abstract

Yu YY, Netuschil N, Lybarger L, Connolly JM, Hansen TH.. Cutting Edge: Single chain trimers of MHC-I molecules form stable structures that potently stimulate antigen-specific T cells and B cells.. J Immunol 168:3145-3149, 2002 Abstract

Hornell TM, Martin SM, Myers NB, Connolly JM.. Peptide length variants p2Ca and QL9 present distinct conformations to Ld-specific T cells.. J Immunol 167:4207-4214, 2001 Abstract

Myers NB, Harris MR, Connolly JM, Lybarger L, Yu YY, Hansen TH.. Kb, Kd, and Ld molecules share common tapasin-dependencies as determined using a novel epitope tag.. J Immunol 165:5656-5663, 2000 Abstract

Hornell TM, Solheim JC, Myers NB, Gillanders WE, Balendiran GK, Hansen TH, Connolly JM.. Alloreactive and syngeneic cytotoxic T lymphocytes are comparably dependent on interaction with MHC class I a-helical residues.. . J Immunol 163:3217-3225, 1999 Abstract

Cook JR, Wormstall EM, Hornell T, Russell J, Connolly JM, Hansen TH.. Quantitation of the cell surface level of Ld resulting in positive vs. negative selection of the 2C transgenic T cell receptor in vivo.. Immunity 7:233-241, 1997 Abstract

Connolly JM.. The p2Ca peptide is immunodominant in allorecognition of Ld by b chain variable region Vb8+ but not Vb8- strains.. Proc Natl Acad Sci USA 91:11482-11486, 1994 Abstract

Alexander-Miller M, Robinson RA, Smith JD, Gillanders WE, Harrison LG, Hansen TH, Connolly JM, Lee D. Definition of T cell receptor recognition sites on Ld-tum- complexes.. Int Immunol 6:1699-1707, 1994 Abstract

Goss JA, Alexander-Miller MA, Gorka J, Flye MW, Connolly JM, Hansen TH.. TCR-derived peptide specifically prolongs allograft survival.. Proc Natl Acad Sci USA 90:9872-9876, 1993 Abstract

Alexander-Miller MA, Burke K, Koszinowski UH, Hansen TH, Connolly JM.. Alloreactive cytotoxic T Lymphocytes generated in the presence of viral-derived peptides show exquisite peptide and MHC specificity.. J Immunol 151:1-10, 1993 Abstract

Solheim JC, Alexander-Miller M, Martinko JM, Connolly JM.. Biased T cell receptor usage by Ld-restricted, tum- peptide-specific cytotoxic T lymphocyte clones.. J Immunol 150:800-811, 1993 Abstract

Goss JA, Pyo R, Flye MW, Connolly JM, Hansen TH.. MHC specific prolongation of murine skin and cardiac allograft survival after in vivo depletion of Vb8+ T cells.. J Exp Med 177:35-44, 1993 Abstract

Alexander MA, Damico CA, Wieties K, Hansen TH, Connolly JM.. Correlation between CD8 dependency and determinant density using peptide-induced, Ld-restricted cytotoxic T lymphocytes.. J Exp Med 173:849-858, 1991 Abstract

Lie WR, Myers NB, Connolly JM, Gorka J, Lee DR, Hansen TH.. The specific binding of peptide ligand to class I MHC molecules determines their antigenic structure.. J Exp Med 173:449-459, 1991 Abstract

Lie WR, Myers NB, Gorka J, Rubocki RJ, Connolly JM, Hansen TH.. Peptide ligand induced conformation and surface expression of the Ld class I MHC molecule.. Nature 344:439-441, 1990 Abstract

Connolly JM, Hansen TH, Ingold AL, Potter TA.. Recognition by CD8 on cytotoxic T lymphocytes is ablated by several substitutions in the class I a3 domain: CD8 and the T cell receptor recognize the same class I molecule.. Proc Natl Acad Sci USA 87:2137-2141, 1990 Abstract

Connolly JM, Potter TA, Wormstall EM, Hansen TH.. The Lyt-2 molecule recognizes residues in the class I a3 domain in allogeneic cytotoxic T-cell responses.. J Exp Med 168:325-341, 1988 Abstract


Current Trainees

Baomei Wang

Past Trainees

Steven Truscott, PhD