Transfer of allograft specific tolerance requires CD4+CD25+T cells but not interleukin-4 or transforming growth factor-beta and cannot induce tolerance to linked antigens.
BACKGROUND
The mechanisms by which CD4+T cells, especially CD4+ CD25+T cells, transfer allograft specific tolerance are poorly defined. The role of cytokines and the effect on antigen-presenting cells is not resolved.


METHODS
Anti-CD3 monoclonal antibody (mAb) therapy induced tolerance to PVG heterotopic cardiac transplantation in DA rats. Peripheral CD4+T cells or CD4+ CD25+ and CD4+ CD25-T cell subsets were adoptively transferred to irradiated DA hosts grafted with PVG heart grafts. For specificity studies, tolerant CD4+T cells were transferred to hosts with Lewis or (PVGxLewis)F1 heart grafts. Cytokine mRNA induction and the requirement for interleukin (IL)-4 and transforming growth factor (TGF)-beta in the transfer of tolerance was assessed.


RESULTS
CD4+T cells transferred specific tolerance and suppressed naïve CD4+T cells capacity to effect rejection of PVG but not Lewis grafts. (PVGxLewis)F1 grafts had a major rejection episode but recovered. Later these hosts accepted PVG but not Lewis skin grafts. Adoptive hosts restored with tolerant or naïve cells had similar levels of mRNA expression for all Th1 and Th2 cytokines and effector molecules assayed. Transfer of tolerance by CD4+T cells was not blocked by mAb to IL-4 or TGF-beta. CD4+ CD25-T cells from either naïve or tolerant hosts effected rejection. In contrast neither tolerant nor naïve CD4+ CD25+T cells restored rejection.


CONCLUSIONS
Specific tolerance transfer required CD4+ containing CD4+ CD25+T cells. An inflammatory response with induction of mRNA for Th1 and Th2 cytokines plus cytotoxic effector molecules occurred, but IL-4 and TGF-beta were not essential. Inhibition of antigen presenting cells was not the sole mechanism as there was no linked tolerance.
Hall
Bruce M
BM
Immune Tolerance Laboratory, University of New South Wales, Australian Technology Park, New South Wales, Australia. b.hall@unsw.edu.au
Plain
Karren M
KM
Verma
Nirupama D
ND
Tran
Giang T
GT
Boyd
Rochelle
R
Robinson
Catherine M
CM
Nicolls
Mark R
MR
Berger
Manuela E
ME
Nomura
Masaru
M
Hodgkinson
Suzanne J
SJ
D000375:Aging / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D000941:Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D016038:Skin Transplantation / Q000276:immunology; D015996:Survival Rate; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
D000941:Antigens; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D015847:Interleukin-4