Cytotoxic T lymphocytes (CTLs) that have been exposed for several days to high concentrations of IL-2 either in vitro or in vivo become highly granular in nature. Considerable attention has been focused on the possibility that these IL-2 induced granules might contain a cytotoxin that could explain how CTLs kill their target cells. How such a mechanism would fit into CTL killing in general is still controversial. What cannot be questioned, however, is that CTLs do not undergo a degranulation process during target cell killing. The contents of CTL granules have been only crudely analyzed. While it is certain that a number of different serine esterases reside in granules, little else is known. We recently began an extensive search for biologically interesting activities released during CTL degranulation. We have defined three activities functionally, and now propose detailed biological, biochemical and molecular genetic analyses of these activities. The three activities we have defined are: CTL inhibition, which is probably a feedback regulatory mechanism for controlling CTL function; T helper cell inhibitin, which may be involved in CD8+ T cell suppression of helper function; and viral inhibitin, which drastically inhibits the ability of mature viral particles to infect cells. Understanding the biochemical basis of these activities will greatly broaden our understanding of CTL function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI014747-19
Application #
3125853
Study Section
Experimental Immunology Study Section (EI)
Project Start
1978-09-30
Project End
1993-05-31
Budget Start
1991-12-01
Budget End
1993-05-31
Support Year
19
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Arts and Sciences
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Ratner, A; Clark, W R (1993) Role of TNF-alpha in CD8+ cytotoxic T lymphocyte-mediated lysis. J Immunol 150:4303-14
Ratner, A; Clark, W R (1991) Lack of target cell participation in cytotoxic T lymphocyte-mediated lysis. J Immunol 147:55-9
Ostergaard, H L; Clark, W R (1989) Evidence for multiple lytic pathways used by cytotoxic T lymphocytes. J Immunol 143:2120-6
Torbett, B E; Clark, W R (1988) The role of accessory molecules in T-helper activation induced by antigen, lectin, or CD3 antibodies. Cell Immunol 115:352-62
Gorman, K; Liu, C C; Blakely, A et al. (1988) Cloned cytotoxic T lymphocytes as target cells. II. Polarity of lysis revisited. J Immunol 141:2211-5
Ostergaard, H; Gorman, K; Clark, W R (1988) Cloned cytotoxic T lymphocyte target cells fail to induce early activation events in effector cytotoxic T lymphocytes. Cell Immunol 114:188-97
Gorman, K C; Kane, K P; Clark, W R (1987) Target cell recognition structures in LDCC and ODCC. J Immunol 138:1014-9
Blakely, A; Gorman, K; Ostergaard, H et al. (1987) Resistance of cloned cytotoxic T lymphocytes to cell-mediated cytotoxicity. J Exp Med 166:1070-83
Young, J D; Clark, W R; Liu, C C et al. (1987) A calcium- and perforin-independent pathway of killing mediated by murine cytolytic lymphocytes. J Exp Med 166:1894-9
Torbett, B E; Skidmore, B; Clark, W R (1986) Multiple pathways for antigen-independent activation of a T helper hybridoma. Eur J Immunol 16:933-8

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