Role of reentry of in vivo alloMHC peptide-activated T cells into the adult thymus in acquired systemic tolerance.
BACKGROUND
T cell recognition of alloMHC peptide presented by self dendritic cells via the indirect pathway of allorecognition in the thymus induces T cell tolerance. Most recently we have shown that the i.v. administration of immunodominant Wistar Furth MHC class I (RT1.Au) peptide 5- (P5) pulsed myeloid or lymphoid dendritic cells induces operational tolerance to a fully MHC-mismatched cardiac allograft. This finding led us to hypothesize that circulation of peripheral P5-activated T cells to the thymus plays an important role in the induction of acquired tolerance.


METHODS
We used the adoptive transfer of 111Indium-oxine- (111In-oxine) labeled P5-pulsed syngeneic dendritic cells and in vivo P5-activated syngeneic T cells to study the role of their circulation to the thymus in the induction of transplantation tolerance.


RESULTS
Intravenously administered 111In-oxine-labeled naïve DC actively migrated to and localized in the liver and spleen but did not enter the lymph nodes, bone marrow, and thymus. In vitro peptide-pulsed dendritic cells had a similar pattern of tissue localization except for a modest number of myeloid but not lymphoid DC entering the thymus. The demonstration that adoptive transfer of in vivo peptide-primed T cells induces permanent graft survival in antilymphocyte serum transiently immunosuppressed syngeneic secondary hosts led us to examine the traffic of in vivo activated T cells. Whereas naïve syngeneic T cells preferentially homed to the peripheral lymphoid organs, they did not reenter the thymus. In contrast, in vivo peptide-activated peripheral T cells migrated to and accumulated in the thymus, thus confirming that reentry of T cells to the thymus is restricted to in vivo activated T cells. Although antilymphocyte serum immunosuppression significantly reduced circulation of primed T cells to the thymus, it did not completely abolish it, as seen with gamma-irradiated primed T cells.


CONCLUSIONS
These findings provide the first formal evidence directly linking reentry of in vivo alloMHC peptide-activated T cells to the thymus with the induction and possibly maintenance of acquired antigen-specific tolerance. Our results suggest that the thymus is open to a two-way traffic with the periphery and may function as a repository of immunological memory.
Gopinathan
R
R
Department of Surgery, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
DePaz
H A
HA
Oluwole
O O
OO
Ali
A O
AO
Garrovillo
M
M
Engelstad
K
K
Hardy
M A
MA
Oluwole
S F
SF
D019264:Adoptive Transfer; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D007108:Immune Tolerance / Q000502:physiology*; D007205:Indium Radioisotopes; D007700:Kinetics; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex / Q000276:immunology*; D009942:Organometallic Compounds; D015125:Oxyquinoline / Q000031:analogs & derivatives*; D051381:Rats; D011912:Rats, Inbred ACI; D011920:Rats, Inbred WF; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology*; D014185:Transplantation, Isogeneic / Q000276:immunology
D007205:Indium Radioisotopes; D009942:Organometallic Compounds; C032950:indium oxine; D015125:Oxyquinoline