T Cell Receptor Molecular Structure and Expression

Hedrick, Stephen

Abstract

The process of T-cell development depends upon both positive and negative selection to produce a population of T-cells that are reactive with foreign, but not self peptides in association with self-encoded MHC molecules. Experiments are proposed to characterize the signal transduction pathways that contribute to or determine the fate of developing thymocytes: either apoptotic death, or differentiation into CD4 or CD8 positive T-cells.
In Aim 1 experiments are proposed to determine how the MAP kinase-related molecules, Erk, JNK, and p38 affect positive and negative selection. Transgenic mice will be produced that express either constitutive or inducible forms of signaling intermediates which cause induction and nuclear translocation of one of these three serine/threonine kinases. The analysis will determine the quantitative effects on both positive and negative selection, and the differential effects on maturation into either CD4 or CD8 positive T-cells. Biochemical analyses will determine the basal level and inducible activity of the parallel Map Kinase pathways.
In Aim 2 the observation that a dominant interfering form of an atypical PKC can enhance negative selection will be investigated. The effects of this mutation on intermediates in the Ras-Erk pathway will be investigated. In addition mice with a targeted deletion in the gene encoding this molecule will be produced and the effects of this deletion on thymocyte development will be determined.
In Aim 3 the role of a calcium-calmodulin induced phosphatase, calcineurin, and kinase, CamKIIg will be investigated. Calcium-independent form of calcineurin can affect the efficiency of positive selection. the effect of this transgene on positive and negative selection, and on the activation of downstream effector molecules, such as members of the NF-AT family will be characterized. Thymic development is one of the most carefully studied models of cellular differentiation in a mammalian organism and, as such, it is important not only in understanding the function and selection of the immune system, but also as a model for cellular differentiation.

Funding Agency

Agency: National Institute of Health (NIH)
Institute: National Institute of Allergy and Infectious Diseases (NIAID)
Type: Method to Extend Research in Time (MERIT) Award (R37)
Project #: 5R37AI021372-18
Application #: 6373049
Study Section: Experimental Immunology Study Section (EI)
Program Officer: Nabavi, Nasrin N

Project Start: 1984-07-01
Project End: 2002-04-30
Budget Start: 2001-05-01
Budget End: 2002-04-30
Support Year: 18
Fiscal Year: 2001
Total Cost: $364,821
Indirect Cost

Institution

Name: University of California San Diego
Department: Internal Medicine/Medicine
Type: Schools of Medicine
DUNS #: 077758407

City: La Jolla
State: CA
Country: United States
Zip Code: 92093

Related projects


NIH 2006 R37 AI	T Cell Receptor Molecular Structure And Expression Hedrick, Stephen M. / University of California San Diego	$366,888
NIH 2005 R37 AI	T Cell Receptor Molecular Structure And Expression Hedrick, Stephen M. / University of California San Diego	$375,717
NIH 2004 R37 AI	T Cell Receptor Molecular Structure And Expression Hedrick, Stephen M. / University of California San Diego	$375,717
NIH 2003 R37 AI	T Cell Receptor Molecular Structure And Expression Hedrick, Stephen M. / University of California San Diego	$375,717
NIH 2002 R37 AI	T Cell Receptor Molecular Structure And Expression Hedrick, Stephen M. / University of California San Diego	$375,717
NIH 2001 R37 AI	T Cell Receptor Molecular Structure and Expression Hedrick, Stephen M. / University of California San Diego	$364,821
NIH 2000 R37 AI	T Cell Receptor Molecular Structure and Expression Hedrick, Stephen M. / University of California San Diego	$429,196
NIH 1999 R37 AI	T Cell Receptor Molecular Structure and Expression Hedrick, Stephen M. / University of California San Diego
NIH 1998 R37 AI	T Cell Receptor Molecular Structure and Expression Hedrick, Stephen M. / University of California San Diego
NIH 1997 R37 AI	T Cell Receptor Molecular Structure and Expression Hedrick, Stephen M. / University of California San Diego

Publications

D'Souza, Warren N; Hedrick, Stephen M (2006) Cutting edge: latecomer CD8 T cells are imprinted with a unique differentiation program. J Immunol 177:777-81

McGargill, Maureen A; Sharp, Leslie L; Bui, Jack D et al. (2005) Active Ca2+/calmodulin-dependent protein kinase II gamma B impairs positive selection of T cells by modulating TCR signaling. J Immunol 175:656-64

Catlett, Ian M; Hedrick, Stephen M (2005) Suppressor of cytokine signaling 1 is required for the differentiation of CD4+ T cells. Nat Immunol 6:715-21

Fischer, April M; Katayama, Carol D; Pages, Giles et al. (2005) The role of erk1 and erk2 in multiple stages of T cell development. Immunity 23:431-43

Soloff, Rachel S; Katayama, Carol; Lin, Meei Yun et al. (2004) Targeted deletion of protein kinase C lambda reveals a distribution of functions between the two atypical protein kinase C isoforms. J Immunol 173:3250-60

Page, D M (1999) Cutting edge: thymic selection and autoreactivity are regulated by multiple coreceptors involved in T cell activation. J Immunol 163:3577-81

Sharp, L L; Hedrick, S M (1999) Commitment to the CD4 lineage mediated by extracellular signal-related kinase mitogen-activated protein kinase and lck signaling. J Immunol 163:6598-605

Hedrick, S M; Sharp, L L (1998) T-cell fate. Immunol Rev 165:95-110

Sharp, L L; Schwarz, D A; Bott, C M et al. (1997) The influence of the MAPK pathway on T cell lineage commitment. Immunity 7:609-18

Kersh, G J; Hooshmand, F F; Hedrick, S M (1995) Efficient maturation of alpha beta lineage thymocytes to the CD4+CD8+ stage in the absence of TCR-beta rearrangement. J Immunol 154:5706-14

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