Many pathogenic bacteria invade and multiply within cells. T lymphocytes are critical for an effective immune response to these intracellular pathogens. Infected cells process and present bacterial antigens to T lymphocytes using mechanisms that are interesting and incompletely understood. An excellent model of cellular immunity and bacterial antigen processing is the murine immune response to Listeria monocytogenes. CD8+ cytotoxic T lymphocytes (CTL) are important effectors of immunity to L. monocytogenes infection and recognize bacterial peptides presented by MHC class l molecules on the surface of infected cells. The peptide specificity of three CTL clones has recently been identified. LLO 91-99 derives from the secreted virulence factor listeriolysin and P6O 217-225 comes from the secreted P6O protein. Both are presented to CTL by the H- 2Kd MHC class l molecule. The third epitope, Fr38, is a secreted bacterial peptide that is presented to CTL by the H-2M3 non-classical MHC class l molecule. Preliminary studies show that these three epitopes appear in L. monocytogenes infected cells at different times and in markedly different quantities, and thus their relative contributions to the protective immune response may differ. The proposed studies will investigate the processing and presentation of the three L. monocytogenes CTL epitopes. The effect of cellular infection on MHC class l antigen processing and presentation will be determined. The possibility that the differences between these CTL epitopes may be of relevance to protective immunity will be explored. These studies will enhance our understanding of the CTL response to intracellular pathogens and may suggest new strategies for protection from intracellular pathogens. Additionally, these studies will increase our understanding of the interactions of pathogenic organisms with their mammalian hosts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI033143-02
Application #
2068138
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1994-07-01
Project End
1999-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Busch, D H; Kerksiek, K M; Pamer, E G (2000) Differing roles of inflammation and antigen in T cell proliferation and memory generation. J Immunol 164:4063-70
Busch, D H; Pamer, E G (1999) T cell affinity maturation by selective expansion during infection. J Exp Med 189:701-10
Busch, D H; Kerksiek, K; Pamer, E G (1999) Processing of Listeria monocytogenes antigens and the in vivo T-cell response to bacterial infection. Immunol Rev 172:163-9
Vijh, S; Pilip, I M; Pamer, E G (1999) Noncompetitive expansion of cytotoxic T lymphocytes specific for different antigens during bacterial infection. Infect Immun 67:1303-9
Busch, D H; Pamer, E G (1999) T lymphocyte dynamics during Listeria monocytogenes infection. Immunol Lett 65:93-8
Busch, D H; Pilip, I M; Vijh, S et al. (1998) Coordinate regulation of complex T cell populations responding to bacterial infection. Immunity 8:353-62
Busch, D H; Pilip, I; Pamer, E G (1998) Evolution of a complex T cell receptor repertoire during primary and recall bacterial infection. J Exp Med 188:61-70
Busch, D H; Pamer, E G (1998) MHC class I/peptide stability: implications for immunodominance, in vitro proliferation, and diversity of responding CTL. J Immunol 160:4441-8
Vijh, S; Pilip, I M; Pamer, E G (1998) Effect of antigen-processing efficiency on in vivo T cell response magnitudes. J Immunol 160:3971-7
Busch, D H; Bouwer, H G; Hinrichs, D et al. (1997) A nonamer peptide derived from Listeria monocytogenes metalloprotease is presented to cytolytic T lymphocytes. Infect Immun 65:5326-9

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