Soluble CD8 stabilizes the HLA class I molecule by promoting beta2M exchange: analysis in real-time.
Human soluble CD8 (sCD8) is secreted by activated CD8+/- cytotoxic T lymphocytes (CTLs). The immunological role of sCD8 is poorly defined, however. We have studied the influence of sCD8 on HLA class I interactions by real-time analysis. Using an optical biosensor we demonstrated that the binding of sCD8 to HLA-A2 promotes exchange of beta2-microglobulin (beta2m) in order to stabilize the complex. Kinetic analysis showed that sCD8 significantly increased the affinity (K(A)) of HLA-A2 for immobilized human beta2m; from 1.14 +/- 0.04 x 10(9) M(-1) in its absence, to 2.18 +/- 0.21 x 10(9) M(-1) following preincubation with sCD8. This suggests that the sCD8:HLA class I complex is unlikely to be degraded at the cell surface. Even in the presence of exogenous peptide (HLA-A2 specific or nonspecific), sCD8 has a stabilizing influence on the HLA class I molecule. These findings point to an immunosuppressive role for sCD8, because the binding of sCD8 to HLA class I would block the binding site for CTL-bound CD8 and, therefore, interfere with T cell activation and proliferation. This may have particular significance in pathological situations where elevated levels of sCD8 are found in extracellular fluids, and sCD8 may provide an alternative approach for immunosuppressive therapy.
Morgan
C L
CL
Anthony Nolan Research Institute, The Royal Free Hospital, London, UK. clmorgan@rfhsm.ac.uk
Price
C P
CP
Cohen
S B
SB
Madrigal
J A
JA
Newman
D J
DJ
D016827:CD8 Antigens / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007165:Immunosuppression Therapy; D013997:Time Factors; D001613:beta 2-Microglobulin / Q000378:metabolism*
D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D001613:beta 2-Microglobulin