De novo-developed T cells have compromised response to existing alloantigens: using Ld-specific transgenic 2C T cells as tracers in a mouse heart transplantation model.
In this study, the phenotype, TCR signaling events, and function of T cells developed de novo during adulthood in the presence of extrathymic alloantigen were investigated. C57BL/6 mice(H-2b) were first transplanted heterotopically with BALB/c hearts (H-2d) and treated with rapamycin for 2 wk to create a tolerant status. Three weeks postoperation, the mice were whole body irradiated and transplanted with bone marrow cells from 2C mice, which are transgenic for TCR, and most of their T cells are Ld-specific CD8 cells. The 2C T cells developed de novo in the C57BL/6 mice were not able to reject the heart allograft. No clonal deletion, TCR down-regulation, or CD8 down-regulation was found in the tolerized 2C T cells. There was no characteristic phenotype of these cells in terms of CD25, ICAM-1, CD44, and MEL-14 expression. Early TCR signaling events such as intracellular calcium concentration flux, tyrosine phosphorylation, Lck and Fyn kinase activities, and Lck and Fyn protein levels in the tolerized 2C T cells were comparable to their normal counterparts, but the tolerized T cells were defective in IL-2 production and proliferation upon H-2d alloantigen stimulation in vitro. Exogenous IL-2 could not reverse the compromised proliferation. The results of this study indicate that during adulthood, the de novo-developed T cells become tolerant to extrathymic Ag without clonal deletion. These newly minted T cells are functionally defective although they are indistinguishable from normal T cells in phenotypes and in some early signaling events.
Luo
H
H
The Louis-Charles Simard Research Center, Notre-Dame Hospital, CHUM, University of Montreal, Quebec, Canada.
Chen
H
H
Qi
S
S
Loh
D
D
Daloze
P
P
Veillette
A
A
Xu
D
D
Wu
J
J
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006183:H-2 Antigens / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D018960:Hyaluronan Receptors / Q000032:analysis; D007108:Immune Tolerance; D016867:Immunocompromised Host / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007376:Interleukin-2 / Q000096:biosynthesis; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011828:Radiation Chimera; D015375:Receptors, Interleukin-2 / Q000032:analysis; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000637:transplantation*
D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D018960:Hyaluronan Receptors; D007376:Interleukin-2; D007519:Isoantigens; D015375:Receptors, Interleukin-2; D018799:Intercellular Adhesion Molecule-1