Antigen-specific help is an essential feature of acquired immunity. The regulated differentiation of type 1 and type 2 cytokine production (IFN- gamma versus IL-4, IL-5-dominated, respectively) and help, in turn, determine susceptibility to microbes, autoimmunity, and allergic inflammation. Although type 1 and type 2 cytokine production appear to be uncoupled in many disease, experimental and genetic manipulations typically have cause reciprocal effects of Th1 and Th2 cells. To investigate the regulation of antigen-specific T cells responses and disease susceptibility, we have created two new transgenic mouse models. As a focus for studying immuno-regulation in a disease-related context, we will employ a mouse model of antigen-inducible airway hyper-responsiveness (AHR). Cytokines characteristic of type 2 T cells (IL-4 and IL-5) are crucial pathogenic components in the inflammation association with allergic airway disease and AHR. Because so many known features of these allergic processes can be produced by Th2-dependent cytokines, asthma has been increasingly viewed as """"""""a Th2 disease."""""""" However, other findings indicate that Th2 cells may not fully account for the T cell contribution to allergic inflammation. The overall goal of the proposed research is to dissect additional immunologic mechanisms that contribute to the development of antigen-inducible AHR. A key hypothesis is that activation of T cells in addition to those which provide type 2 help is essential for the full development of AHR. This hypothesis will be tested using transgenes whose expression is targeted to the T lineage. Our transgene encodes a chimeric cytokine receptor, so that IL-2 binding to activated T cells leads to intracellular signaling characteristic of IL-4 as well as IL-2, and type 2 help is selectively enhanced. Experiments in Specific Aims 1 and 2 will investigate immunologic consequences of this immune deviation and determine if it is sufficient to overcome completely the lower responder phenotype of C57BL mice in the OVA-induced AHR model. The other transgene [IkappaBalpha(deltaN)] inhibits signaling through the NF- kappaB/Rel pathway in T cells. Surprisingly, the observed inhibition of OVA-inducible AHR was accompanied by evidence of intact type 2 help despite inhibition of type 1 help. Experiments proposed in Specific Aim 3 will measure Th1 and Th2 development in vivo and investigate the requirement for cells other than type 2 helper cells in AHR. We will use T cell transfer experiments to determine if restoration of type 1 help is sufficient (Stat6-deficient T cells) or necessary (using IRF-1-deficient CD4+ T cells) to restore AHR susceptibility in IkappaBalpha (deltaN) mice, and elucidate the requirement for functional CD8+ cells in this system.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061752-03
Application #
6330188
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Noel, Patricia
Project Start
1998-12-16
Project End
2002-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
3
Fiscal Year
2001
Total Cost
$276,281
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Talati, Megha; Meyrick, Barbara; Peebles Jr, R Stokes et al. (2006) Oxidant stress modulates murine allergic airway responses. Free Radic Biol Med 40:1210-9
Aronica, Mark A; Swaidani, Shadi; Zhang, Yan H et al. (2004) Susceptibility to allergic lung disease regulated by recall responses of dual-receptor memory T cells. J Allergy Clin Immunol 114:1441-8
Stanic, Aleksandar K; Bezbradica, Jelena S; Park, Jang-June et al. (2004) Cutting edge: the ontogeny and function of Va14Ja18 natural T lymphocytes require signal processing by protein kinase C theta and NF-kappa B. J Immunol 172:4667-71
Stanic, Aleksandar K; Bezbradica, Jelena S; Park, Jang-June et al. (2004) NF-kappa B controls cell fate specification, survival, and molecular differentiation of immunoregulatory natural T lymphocytes. J Immunol 172:2265-73
Aronica, Mark A; McCarthy, Susan; Swaidani, Shadi et al. (2004) Recall helper T cell response: T helper 1 cell-resistant allergic susceptibility without biasing uncommitted CD4 T cells. Am J Respir Crit Care Med 169:587-95
Liang, Yurong; Christopher, Kenneth; DeFina, Rachel et al. (2003) Analysis of cytokine functions in graft rejection by gene expression profiles. Transplantation 76:1749-58
Kelly-Welch, Ann E; Hanson, Erica M; Boothby, Mark R et al. (2003) Interleukin-4 and interleukin-13 signaling connections maps. Science 300:1527-8
Mora, A L; Corn, R A; Stanic, A K et al. (2003) Antiapoptotic function of NF-kappaB in T lymphocytes is influenced by their differentiation status: roles of Fas, c-FLIP, and Bcl-xL. Cell Death Differ 10:1032-44
Finn, Patricia W; He, Hongzhen; Ma, Chunyan et al. (2002) Molecular profiling of the role of the NF-kappaB family of transcription factors during alloimmunity. J Leukoc Biol 72:1054-62
Chen, Ying; Rosloniec, Ed; Price, Jim et al. (2002) Constitutive expression of BCL-X(L) in the T lineage attenuates collagen-induced arthritis in Bcl-X(L) transgenic mice. Arthritis Rheum 46:514-21

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