ABCMdb

ABCB2 p.Val405Leu

Predicted by SNAP2:	A: N (72%), C: N (78%), D: D (63%), E: D (53%), F: N (78%), G: N (53%), H: N (78%), I: N (82%), K: N (53%), L: N (93%), M: N (87%), N: N (61%), P: D (59%), Q: N (66%), R: N (61%), S: N (72%), T: N (78%), W: N (57%), Y: N (87%),
Predicted by PROVEAN:	A: N, C: N, D: D, E: N, F: N, G: D, H: N, I: N, K: N, L: N, M: N, N: N, P: D, Q: N, R: N, S: N, T: N, W: N, Y: N,

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[hide] Inefficient cross-presentation limits the CD8+ T c... J Immunol. 2005 Jul 15;175(2):700-12. Otahal P, Hutchinson SC, Mylin LM, Tevethia MJ, Tevethia SS, Schell TD
Inefficient cross-presentation limits the CD8+ T cell response to a subdominant tumor antigen epitope.
J Immunol. 2005 Jul 15;175(2):700-12., [PMID:16002665]

Abstract [show]
CD8(+) T lymphocytes (T(CD8)) responding to subdominant epitopes provide alternate targets for the immunotherapy of cancer, particularly when self-tolerance limits the response to immunodominant epitopes. However, the mechanisms that promote T(CD8) subdominance to tumor Ags remain obscure. We investigated the basis for the lack of priming against a subdominant tumor epitope following immunization of C57BL/6 (B6) mice with SV40 large tumor Ag (T Ag)-transformed cells. Immunization of B6 mice with wild-type T Ag-transformed cells primes T(CD8) specific for three immunodominant T Ag epitopes (epitopes I, II/III, and IV) but fails to induce T(CD8) specific for the subdominant T Ag epitope V. Using adoptively transferred T(CD8) from epitope V-specific TCR transgenic mice and immunization with T Ag-transformed cells, we demonstrate that the subdominant epitope V is weakly cross-presented relative to immunodominant epitopes derived from the same protein Ag. Priming of naive epitope V-specific TCR transgenic T(CD8) in B6 mice required cross-presentation by host APC. However, robust expansion of these T(CD8) required additional direct presentation of the subdominant epitope by T Ag-transformed cells and was only significant following immunization with T Ag-expressing cells lacking the immunodominant epitopes. These results indicate that limited cross-presentation coupled with competition by immunodominant epitope-specific T(CD8) contributes to the subdominant nature of a tumor-specific epitope. This finding has implications for vaccination strategies targeting T(CD8) responses to cancer.

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157 Table I. SV40 T Ag-transformed cell lines used in this study Cell Designation Cell Type Transforming Agent T Ag Construct H-2b CTL Epitopes Present References B6/T5Aa C57BL/6 embryo fibroblasts pLM234 WT I, II/III, IV, V 30 B6/T116A1 C57BL/6 embryo fibroblasts pSLM361-11 èc;207-215, èc;223-231, Y406A, F408A, C411A (V-only T Ag) V 31 B6/K-0 C57BL/6 kidney pPVU0 WT I, II/III, IV, V 45 B6/K-1,4a C57BL/6 kidney Derived from K-0 èc;134-263, V405L V 45 B6/K-1,4-SVb C57BL/6 kidney Derived from K-1,4 af9; pSV2neo-SV40 èc;134-263, V405L T Ag af9; WT I, II/III, IV, V 45 B6/122B1 (B6 èc;I, II/III, IV, V T Ag) C57BL/6 embryo fibroblasts PLMTS364-1 N210A, N227A, F408A, N493A (no CTL epitopes) None 31 TAP1afa;/afa; wt B6.129S2-Tap1tm1Arp kidney pPVU0 WT I, II/III, IV, V This study TAP1afa;/afa; 361-11 B6.129S2-Tap1tm1Arp kidney pSLM361-11 èc;207-215, èc;223-231, Y406A, F408A, C411A (V-only T Ag) V This study a K-0 epitope loss variant selected by coculture with T Ag-specific CTL clones in vitro. Login to comment