title: Myeloma-induced alloreactive T cells arising in myeloma-infiltrated bones include double-positive CD8+CD4+ T cells: evidence from myeloma-bearing mouse model.
abstract: The graft-versus-myeloma (GVM) effect represents a powerful form of immune attack exerted by alloreactive T cells against multiple myeloma cells, which leads to clinical responses in multiple myeloma transplant recipients. Whether myeloma cells are themselves able to induce alloreactive T cells capable of the GVM effect is not defined. Using adoptive transfer of T naive cells into myeloma-bearing mice (established by transplantation of human RPMI8226-TGL myeloma cells into CD122(+) cell-depleted NOD/SCID hosts), we found that myeloma cells induced alloreactive T cells that suppressed myeloma growth and prolonged survival of T cell recipients. Myeloma-induced alloreactive T cells arising in the myeloma-infiltrated bones exerted cytotoxic activity against resident myeloma cells, but limited activity against control myeloma cells obtained from myeloma-bearing mice that did not receive T naive cells. These myeloma-induced alloreactive T cells were derived through multiple CD8(+) T cell divisions and enriched in double-positive (DP) T cells coexpressing the CD8αα and CD4 coreceptors. MHC class I expression on myeloma cells and contact with T cells were required for CD8(+) T cell divisions and DP-T cell development. DP-T cells present in myeloma-infiltrated bones contained a higher proportion of cells expressing cytotoxic mediators IFN-γ and/or perforin compared with single-positive CD8(+) T cells, acquired the capacity to degranulate as measured by CD107 expression, and contributed to an elevated perforin level seen in the myeloma-infiltrated bones. These observations suggest that myeloma-induced alloreactive T cells arising in myeloma-infiltrated bones are enriched with DP-T cells equipped with cytotoxic effector functions that are likely to be involved in the GVM effect.
authors: Mater Medical Research Institute, Queensland 4101, Australia.
authors: Lisa M
authors: LM
authors: Freeman
authors: Alfred
authors: A
authors: Lam
authors: Eugene
authors: E
authors: Petcu
authors: Robert
authors: R
authors: Smith
authors: Ali
authors: A
authors: Salajegheh
authors: Peter
authors: P
authors: Diamond
authors: Andrew
authors: A
authors: Zannettino
authors: Andreas
authors: A
authors: Evdokiou
authors: John
authors: J
authors: Luff
authors: Pooi-Fong
authors: PF
authors: Wong
authors: Dalia
authors: D
authors: Khalil
authors: Nigel
authors: N
authors: Waterhouse
authors: Frank
authors: F
authors: Vari
authors: Alison M
authors: AM
authors: Rice
authors: Laurence
authors: L
authors: Catley
authors: Derek N J
authors: DN
authors: Hart
authors: Slavica
authors: S
authors: Vuckovic
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020350:Graft vs Tumor Effect / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000276:immunology*; D014184:Transplantation, Homologous