Multiple pathways are involved in the extracellular processing of MHC class I-restricted peptides.
T cell stimulation by certain class I-restricted antigenic peptides, such as the HIV 1 gp160-derived peptide, P18, requires peptide processing by angiotensin-1 converting enzyme (ACE) in FCS. We observed that longer versions of P18 and the murine cytomegalovirus pp89-derived core peptide, pMCMV, which could stimulate T cell hybridomas in FCS, were not as sensitive to the ACE inhibitor captopril as P18. Using cell-free soluble murine class I MHC molecules and protease inhibitors, we found that there are pathways of differing efficiency that use enzymes other than ACE for the proteolytic processing of peptides in serum. The kinetics of the generation of T cell stimulatory activity among P18 variant peptides in serum differed with peptide length, and with the nature of amino and COOH-terminal extensions. Such processing occurs in human plasma as well as in FCS. The understanding of this processing, its kinetics, and its inhibitors can lead to better design of peptide-based therapies, including vaccines.
Kozlowski
S
S
Molecular Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Corr
M
M
Shirai
M
M
Boyd
L F
LF
Pendleton
C D
CD
Berzofsky
J A
JA
Margulies
D H
DH
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001790:Blood Physiological Phenomena; D002460:Cell Line; D015683:Gene Products, gag / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D054301:gag Gene Products, Human Immunodeficiency Virus
D015683:Gene Products, gag; D015395:Histocompatibility Antigens Class I; D017874:Immediate-Early Proteins; C052612:cytomegalovirus immediate early phosphoprotein pp89; D054301:gag Gene Products, Human Immunodeficiency Virus; C061169:p18 gag protein, Human immunodeficiency virus 1; D007703:Peptidyl-Dipeptidase A