We will analyze the generation and specificity of influenza virus-induced human cytotoxic T lymphocytes (CTL) and interferon gamma. Influenza specific CTL are required for recovery from influenza infection in the murine model. We have demonstrated that lymphocytes of humans produce gamma interferon during the generation of HLA-restricted influenza-specific T lymphocyte responses, and a significant correlation exists between the levels of gamma interferon induced and the CTL response. In the proposed studies we will define the influenza virus antigens responsible for human CTL responses and gamma interferon production. We recently demonstrated a subtype-specific CTL response to an antigenic site on the HA2 subunit in the murine system. This subtype-specific CTL response is broadly cross-reactive within the Hl subtype. In the proposed studies we will determine whether this epitope induces subtype-specific CTL responses from human lymphocytes and determine whether a similar subtype-specific CTL antigenic site is present in viruses of the H3 subtype. The molecule containing the subtype-specific CTL determinant renders murine target cells from H-2d mice susceptible to lysis by influenza specific CTL; however, cells of H-2b or H-2k mice which are susceptible to CTL lysis when infected with virus are not rendered susceptible to lysis by this molecule. We will determine in the murine system the requirements for MHC restrictions of this subtype-specific CTL determinant. Human CTL studies will be done to determine whether specific HLA haplotypes also interact differently with the subtype-specific determinant as recognized by viru-immune CTLs. Studies will be performed using human lymphocytes to determine the precursor frequency of influenza-induced cross-reactive and subtype-specific CTL responses in normal adults, and following vaccination or recent infection. The duration of these CTL responses which are thought to be associated with protection will be determined. The effect of immunization or infection on the production of interferon gamma produced by human T lymphocytes and on the number of human lymphocytes producing interferon gamma will be assessed. The results of these experiments should provide basic insights into our understanding of the specificity and roles of human influenza specific CTLs, and their immunoregulatory relationships with interferon gamma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI019378-04
Application #
3128760
Study Section
Experimental Virology Study Section (EVR)
Project Start
1983-05-01
Project End
1991-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Gotoff, R; Tamura, M; Janus, J et al. (1994) Primary influenza A virus infection induces cross-reactive antibodies that enhance uptake of virus into Fc receptor-bearing cells. J Infect Dis 169:200-3
Tamura, M; Webster, R G; Ennis, F A (1991) Antibodies to HA and NA augment uptake of influenza A viruses into cells via Fc receptor entry. Virology 182:211-9
Kuwano, K; Reyes, V E; Humphreys, R E et al. (1991) Recognition of disparate HA and NS1 peptides by an H-2Kd-restricted, influenza specific CTL clone. Mol Immunol 28:1-7
Kuwano, K; Tamura, M; Ennis, F A (1990) Cross-reactive protection against influenza A virus infections by an NS1-specific CTL clone. Virology 178:174-9
Kuwano, K; Braciale, T J; Ennis, F A (1989) Cytotoxic T lymphocytes recognize a cross-reactive epitope on the transmembrane region of influenza H1 and H2 hemagglutinins. Viral Immunol 2:163-73
Kuwano, K; Scott, M; Young, J F et al. (1989) Active immunization against virus infections due to antigenic drift by induction of crossreactive cytotoxic T lymphocytes. J Exp Med 169:1361-71
Kuwano, K; Scott, M; Young, J F et al. (1988) HA2 subunit of influenza A H1 and H2 subtype viruses induces a protective cross-reactive cytotoxic T lymphocyte response. J Immunol 140:1264-8
Jaffe, P A; Kuwano, K; Yamada, A et al. (1987) Kinetics and specificity at the clonal level of the cytotoxic T lymphocyte response to influenza pneumonia. Viral Immunol 1:259-66
Kurane, I; Meager, A; Ennis, F A (1986) Induction of interferon alpha and gamma from human lymphocytes by dengue virus-infected cells. J Gen Virol 67 ( Pt 8):1653-61
Kurane, I; Hebblewaite, D; Ennis, F A (1986) Characterization with monoclonal antibodies of human lymphocytes active in natural killing and antibody-dependent cell-mediated cytotoxicity of dengue virus-infected cells. Immunology 58:429-36

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