John W. Kappler, Ph.D.
Professor of Immunology Integrated Department (UCHSC/NJMRC)
National Jewish Medical and Research Center
UCHSC Mail Stop A004
1400 Jackson Street
Denver, Colorado 80011
Phone: 303.398.1322
KapplerJ@njc.org
EDUCATION/EXPERIENCE
HONORS AND AWARDS
PROFESSIONAL ACTIVITIES
Research Interests
Our laboratory is involved
in structure/functions studies of the a/b receptor of T cells and of its ligands.
The conventional ligand for this receptor is one of the major histocompatibility
complex proteins (MHC) with a self or foreign peptide held a specialized groove
on the MHC surface. Interaction with this type of ligand determines the fate of
T cells at all stages of differentiation, including initial development in the
thymus as well as subsequent elimination or activation following contact with
MHC occupied by self or foreign peptides.
We also study a second type of ligand composed of an MHC molecule
complexed with any of a set of microbial proteins, collectively called "superantigens"
(SAgs). In this case the antigen binds to an MHC molecule as a protein to a site
distinct from the peptide binding groove. Peptide/MHC ligands interact with the
receptor in a complex way involving the variable loops of the receptor Va and
Vb domains corresponding to the CDR loops of antibodies. Therefore, only the occasional
T cell (~1 per 100,000) has a receptor with the precisely joined combination of
Va, Ja, Vb, Db and Jb required bind the ligand.
On the other hand, SAg/MHC ligands bind to the receptor via
the Vb element only leading to a very high frequency of T cell activation. The
flood of cytokines released during this powerful response is at the root of the
diseases, such as food poisoning and toxic shock, associated with exposure of
the immune system to these proteins. We have developed expression systems for
a/b receptors and MHC molecules which we have used to produce cell-free, soluble
forms of the proteins. In order to express MHC molecules occupied with a single
peptide, we have devised a way to attach sequence encoding a peptide to the MHC
gene, such that the MHC molecule becomes occupied with the peptide during biosynthesis
to the exclusion of all other peptides. We are now using biophysical methods and
X-ray crystallography to study the details of the association of a/b receptors
with both peptide/MHC and SAg/MHC ligands.
We complement these studies with experiments in transgenic
mice, where we can track the influence of a single peptide/MHC molecule on the
development of T cells bearing a particular a/b receptor. We are trying to understand
how the affinities of these interactions contribute to the fate of T cells whose
receptors are engaged at various stages of differentiation.
Selected Publications
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Fasso M, Anandasabapathy N, Crawford F, Kappler J, Fathman
CG, Ridgway WM. T cell receptor (TCR)-mediated repertoire selection
and loss of TCR vbeta diversity during the initiation of a CD4(+)
T cell response In vivo. J Exp Med 2000 Dec 18;192(12):1719-30
[Abstract]
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Kedl RM, Rees WA, Hildeman DA, Schaefer B, Mitchell T, Kappler
J, Marrack P. T cells compete for access to antigen-bearing
antigen-presenting cells. J Exp Med. 2000 Oct 16;192(8):1105-14.
[Abstract]
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Meyer AL, Trollmo C, Crawford F, Marrack P, Steere AC, Huber
BT, Kappler J, Hafler DA. Direct enumeration of borrelia-reactive
CD4 T cells ex vivo by using MHC class II tetramers. Proc Natl
Acad Sci U S A. 2000 Oct 10;97(21):11433-8. [Abstract]
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Jackisch BO, Hausser H, Schaefer L, Kappler J, Muller
HW, Kresse H. Alternative exon usage of rat septins. Biochem
Biophys Res Commun. 2000 Aug 18;275(1):180-8. [Abstract]
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Kappler J, Franken S, Junghans U, Hoffmann R, Linke
T, Muller HW, Koch KW. Glycosaminoglycan-binding properties
and secondary structure of the C-terminus of netrin-1. Biochem
Biophys Res Commun. 2000 May 10;271(2):287-91. [Abstract]
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Ku CC, Murakami M, Sakamoto A, Kappler J, Marrack P.
Control of homeostasis of CD8+ memory T cells by opposing cytokines.
Science. 2000 Apr 28;288(5466):675-8. [Abstract]
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Teague TK, Schaefer BC, Hildeman D, Bender J, Mitchell T, Kappler
JW, Marrack P. Activation-induced inhibition of interleukin
6-mediated T cell survival and signal transducer and activator
of transcription 1 signaling. J Exp Med. 2000 Mar 20;191(6):915-26.
[Abstract]
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Marrack P, Mitchell T, Hildeman D, Kedl R, Teague TK, Bender
J, Rees W, Schaefer BC, Kappler J. Genomic-scale analysis
of gene expression in resting and activated T cells. Curr Opin
Immunol. 2000 Apr;12(2):206-9. Review. [Abstract]
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Kotzin BL, Falta MT, Crawford F, Rosloniec EF, Bill J, Marrack
P, Kappler J. Use of soluble peptide-DR4 tetramers to
detect synovial T cells specific for cartilage antigens in patients
with rheumatoid arthritis. Proc Natl Acad Sci U S A. 2000 Jan
4;97(1):291-6. [Abstract]
Bibliography
Dr.
Kappler's lab web page.
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