The long term objective of this proposal is to understand the physiological consequences of mature T cells contacting antigen in vivo. The proposal focusses on Mls antigens, a class of murine endogenous """"""""superantigens"""""""" encoded by mammary tumor proviral loci. During the current funding period, evidence has been obtained that strong in vivo immune responses to Mls-a-bearing cells are followed by the elimination of most of the responding T cells. One of the major aims of the current proposal is to determine how this occurs. Particular emphasis will be placed on assessing whether elimination is a reflection of overstimulation of T cells by antigen. Other possibilities to be considered include a) that antigen-activated effector T cells are intrinsically short-lived, and b) that activated T cells are destroyed by regulatory/suppressor cells. Various approaches, including a careful characterization of the T cells that escape elimination, will be used to assess these possibilities. Preliminary work suggests that T cell elimination is partly a reflection of cell death per se but is also a reflection of T cell migration to mucosal surfaces. Various experiments are proposed to examine the relative contribution of cell death vs. altered lymphocyte migration to T cell elimination from the lymphoid organs. The type of cell death - apoptosis vs. necrosis - and the influence of cytokines on cell death will be studied. A third major issue to be addressed is the relationship between the induction of T cell anergy vs. T cell elimination. This issue will be examined by defining which particular experimental conditions favor anergy vs. elimination. Here it will be important to examine the role of ligand density and persistence of antigen. Although all of these various studies on T cell tolerance will be centered around Mls antigens, parallel studies will be performed with TCR transgenic T cells responding to a conventional antigen, cytochrome-C. Finally, information will be sought on why Mls-a antigens can be presented by the CD8 subset of T cells, i.e. cells that lack detectable MHC class II molecules. An in vitro model has been developed to study this paradox. Since inappropriate regulation of mature T cell responses is instrumental in a variety of diseases, including malignancy and autoimmunity, defining the factors involved in this regulation is of utmost importance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA041993-07
Application #
3182655
Study Section
Immunobiology Study Section (IMB)
Project Start
1985-07-01
Project End
1998-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Camacho, S A; Heath, W R; Carbone, F R et al. (2001) A key role for ICAM-1 in generating effector cells mediating inflammatory responses. Nat Immunol 2:523-9
Ragazzo, J L; Ozaki, M E; Karlsson, L et al. (2001) Costimulation via lymphocyte function-associated antigen 1 in the absence of CD28 ligation promotes anergy of naive CD4+ T cells. Proc Natl Acad Sci U S A 98:241-6
Ozaki, M E; Webb, S R (2000) Controlling mature CD4+ T cell responses. Immunol Res 21:345-55
Luksch, C R; Winqvist, O; Ozaki, M E et al. (1999) Intercellular adhesion molecule-1 inhibits interleukin 4 production by naive T cells. Proc Natl Acad Sci U S A 96:3023-8
Ozaki, M E; Coren, B A; Huynh, T N et al. (1999) CD4+ T cell responses to CD40-deficient APCs: defects in proliferation and negative selection apply only with B cells as APCs. J Immunol 163:5250-6
Ozaki, M E; Karlsson, L; Peterson, P A et al. (1997) Antigen specificity of dual reactive T hybridomas determines the requirement for CD40 ligand-CD40 interactions. J Immunol 159:214-21
Hartwig, U F; Karlsson, L; Peterson, P A et al. (1997) CD40 and IL-4 regulate murine CD27L expression. J Immunol 159:6000-8
O'Rourke, A M; Webb, S R (1997) Cross talk between T and B cells generates B antigen-presenting cells able to induce inositol phosphate production in T cells responding to Mls(a) superantigens. Eur J Immunol 27:3253-8
Hayden, K A; Tough, D F; Webb, S R (1996) In vivo response of mature T cells to Mlsa antigens. Long-term progeny of dividing cells include cells with a naive phenotype. J Immunol 156:48-55
Sprent, J; Webb, S R (1995) Intrathymic and extrathymic clonal deletion of T cells. Curr Opin Immunol 7:196-205

Showing the most recent 10 out of 25 publications