The proposed studies are aimed at providing a fuller understanding of the regulation and the function of the cytotoxic T lymphocyte (CTL) response. The specific response of murine lymphocytes to allogeneic major (H-2) and minor histocompatibility (H) antigens, and the polyclonal induction of T cells with Con A will be analyzed. The role of soluble factors in the CTL response will be studied. CTL clones specific for H-2 or minor H antigens, which are dependent on both antigen stimulation and IL-2 for continued growth, will be used extensively in this work. The mitogen or antigen induced expression of killing activity by T cell populations which have been depleted of adherent, Ia-positive accessory cells is dependent on a soluble factor other than IL-1 and IL-2 which we refer to as """"""""CTL Differentiation Factor"""""""" (CDF). Experiments are proposed to determine the cellular source of CDF, the stimuli which induce its secretion, at what stage it acts in the CTL response, and to characterize the activity. An effector CTL, capable of lysing target cells, can also secrete immune interferon (IFN) on recognizing antigen. We showed that a number of antigen and IL-2 dependent CTL clones released large amounts of IFN in response to specific antigen or Con A stimulation. The local release of immune IFN may provide another important arm of the CTL effector response. The conditions required to induce IFN release, and whether all CTL, or other T cell types, can secrete IFN will be studied here. Long-term cultures derived from MLC enriched for CTL, as well as cloned, effector CTL may be used for therapeutic functions in the future. We will therefore investigate the ability of cultured CTL to adoptively transfer immunological memory to syngeneic hosts. Conditions which influence the generation of CTL memory cells in vitro and in vivo will be studied. An in vitro assay for lymphocyte homing will be employed to give some indication as to whether cultured CTL will be able to function effectively in vivo.

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 #
5R37AI019335-17
Application #
2330316
Study Section
Special Emphasis Panel (NSS)
Project Start
1990-06-01
Project End
1999-01-31
Budget Start
1997-02-01
Budget End
1999-01-31
Support Year
17
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Bergsbaken, Tessa; Bevan, Michael J (2015) Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8? T cells responding to infection. Nat Immunol 16:406-14
Bergsbaken, Tessa; Bevan, Michael J (2015) Cutting Edge: Caspase-11 Limits the Response of CD8+ T Cells to Low-Abundance and Low-Affinity Antigens. J Immunol 195:41-5
Mehlhop-Williams, Erin R; Bevan, Michael J (2014) Memory CD8+ T cells exhibit increased antigen threshold requirements for recall proliferation. J Exp Med 211:345-56
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Zhang, Nu; Bevan, Michael J (2012) TGF-? signaling to T cells inhibits autoimmunity during lymphopenia-driven proliferation. Nat Immunol 13:667-73
Prlic, Martin; Sacks, Jilian A; Bevan, Michael J (2012) Dissociating markers of senescence and protective ability in memory T cells. PLoS One 7:e32576
Prlic, Martin; Bevan, Michael J (2011) Cutting edge: ?-catenin is dispensable for T cell effector differentiation, memory formation, and recall responses. J Immunol 187:1542-6
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Zhang, Nu; Bevan, Michael J (2010) Dicer controls CD8+ T-cell activation, migration, and survival. Proc Natl Acad Sci U S A 107:21629-34

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