Inactivation of T-cell receptor-mediated integrin activation prolongs allograft survival in ADAP-deficient mice.
BACKGROUND
Signaling through the T cell receptor (TCR) leads to profound changes in the function and properties of T cells, including integrin activation. Adhesion and degranulation promoting adapter protein (ADAP) is an adapter protein linking T cell receptor stimulation to integrin activation. We aim to clarify how disruption of TCR-mediated integrin activation affects alloreactive immune responses.


METHODS
In vitro T cell proliferation and the cytokine production was determined. In vivo cytotoxic T lymphocyte (CTL) activity was measured as well. Allogenic skin and heart transplantation was used to test the in vivo role of ADAP in alloimmune responses. Histology and flow cytometry was applied to analyze the graft infiltrating lymphocytes.


RESULTS
Upon stimulation with allogenic dendritic cells ADAP-deficient T cells displayed impaired proliferative responses compared to wild type (WT) T cells. This was accompanied by significantly decreased production of the cytokine interleukin-2. In contrast, the in vivo CTL activity in ADAP-deficient mice was comparable to that of WT mice. Consistently, we observed a prolongation of fully major histocompatibility complex (MHC)-mismatched heart transplants in ADAP deficient mice. Protection of allogenic heart grafts in ADAP-deficient mice was accompanied by a decrease in the infiltration, proliferation and activation of T cells in the allograft. However, no effect was observed after fully MHC-mismatched skin transplantation.


CONCLUSIONS
We have shown that although ADAP is dispensable for the rejection of allografts, ADAP function plays an important role for the efficacy of graft rejection. ADAP's main function appears to affect the induction phase of the immune response.
Tian
Jiong
J
Kidney Disease Center, The 1st Affiliated Hospital of Zhejiang University, Zhejiang, China.
Pabst
Oliver
O
Römermann
Dorothee
D
Skubich
Susanne
S
Förster
Reinhold
R
Beckmann
Jan
J
Chen
Jiang-Hua
JH
Hoffmann
Matthias W
MW
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology; D049109:Cell Proliferation; D006085:Graft Survival / Q000502:physiology*; D016027:Heart Transplantation / Q000473:pathology / Q000502:physiology*; D016023:Integrins / Q000502:physiology*; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D016038:Skin Transplantation / Q000473:pathology / Q000502:physiology*; D014184:Transplantation, Homologous
D048868:Adaptor Proteins, Signal Transducing; C491468:Fyb protein, mouse; D016023:Integrins; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell