TY - JOUR
T1 - The role of antigen cross-presentation from leukemia blasts on immunity to the leukemia-associated antigen PR1
AU - Alatrash, Gheath
AU - Ono, Yoko
AU - Sergeeva, Anna
AU - Sukhumalchandra, Pariya
AU - Zhang, Mao
AU - St John, Lisa S.
AU - Yang, Tian Hui
AU - Ruisaard, Kathryn
AU - Armistead, Paul M.
AU - Mittendorf, Elizabeth A.
AU - He, Hong
AU - Qiao, Na
AU - Rodriguez-Cruz, Tania
AU - Liang, Shoudan
AU - Clise-Dwyer, Karen
AU - Wieder, Eric D.
AU - Lizee, Gregory
AU - Lu, Sijie
AU - Molldrem, Jeffrey J.
PY - 2012/5
Y1 - 2012/5
N2 - Cross-presentation is an important mechanism by which exogenous tumor antigens are presented to elicit immunity. Because neutrophil elastase (NE) and proteinase-3 (P3) expression is increased in myeloid leukemia, we investigated whether NE and P3 are cross-presented by dendritic cells (DC) and B cells, and whether the NE and P3 source determines immune outcomes. We show that NE and P3 are elevated in leukemia patient serum and that levels correlate with remission status. We demonstrate cellular uptake of NE and P3 into lysosomes, ubiquitination, and proteasome processing for cross-presentation. Using anti-PR1/human leukocyte antigen-A2 monoclonal antibody, we provide direct evidence that B-cells cross-present soluble and leukemia-associated NE and P3, whereas DCs cross-present only leukemia-associated NE and P3. Cross-presentation occurred at early time points but was not associated with DC or B-cell activation, suggesting that NE and P3 cross-presentation may favor tolerance. Furthermore, we show aberrant subcellular localization of NE and P3 in leukemia blasts to compartments that share common elements of the classic major histocompatibility class I antigen-presenting pathway, which may facilitate cross-presentation. Our data demonstrate distinct mechanisms for cross-presentation of soluble and cell-associated NE and P3, which may be valuable in understanding immunity to PR1 in leukemia.
AB - Cross-presentation is an important mechanism by which exogenous tumor antigens are presented to elicit immunity. Because neutrophil elastase (NE) and proteinase-3 (P3) expression is increased in myeloid leukemia, we investigated whether NE and P3 are cross-presented by dendritic cells (DC) and B cells, and whether the NE and P3 source determines immune outcomes. We show that NE and P3 are elevated in leukemia patient serum and that levels correlate with remission status. We demonstrate cellular uptake of NE and P3 into lysosomes, ubiquitination, and proteasome processing for cross-presentation. Using anti-PR1/human leukocyte antigen-A2 monoclonal antibody, we provide direct evidence that B-cells cross-present soluble and leukemia-associated NE and P3, whereas DCs cross-present only leukemia-associated NE and P3. Cross-presentation occurred at early time points but was not associated with DC or B-cell activation, suggesting that NE and P3 cross-presentation may favor tolerance. Furthermore, we show aberrant subcellular localization of NE and P3 in leukemia blasts to compartments that share common elements of the classic major histocompatibility class I antigen-presenting pathway, which may facilitate cross-presentation. Our data demonstrate distinct mechanisms for cross-presentation of soluble and cell-associated NE and P3, which may be valuable in understanding immunity to PR1 in leukemia.
KW - PR1
KW - cross-presentation
KW - leukemia
KW - myeloid
KW - neutrophil elastase
KW - proteinase-3
UR - http://www.scopus.com/inward/record.url?scp=84859919484&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859919484&partnerID=8YFLogxK
U2 - 10.1097/CJI.0b013e31824b3b14
DO - 10.1097/CJI.0b013e31824b3b14
M3 - Article
C2 - 22495388
AN - SCOPUS:84859919484
SN - 1524-9557
VL - 35
SP - 309
EP - 320
JO - Journal of Immunotherapy
JF - Journal of Immunotherapy
IS - 4
ER -