An anti-CD2 monoclonal antibody that both inhibits and stimulates T cell activation recognizes a subregion of CD2 distinct from known ligand-binding sites.
The T lymphocyte glycoprotein CD2 appears to have an important role in human T cell development and activation. A novel anti-CD2 monoclonal antibody, designed UMCD2, was shown to block E rosetting, and therefore was defined as recognizing the Tll1 ligand-binding epitope. Binding of UMCD2 to T cells and thymocytes was blocked by several, but not all, anti-Tll1 antibodies, suggesting that the Tll1 epitope consists of more than one subepitope. In functional studies, the combination of UMCD2 plus anti-Tll3 was mitogenic for T cells; in some individuals, the level of activation was as high as that seen for the combination of anti-Tll2 plus anti-Tll3. However, when UMCD2 was added to other stimuli mitogenic for T lymphocytes, such as IL-2 or anti-CD3-Sepharose, it inhibited T cell responses. Although the combination of UMCD2 and anti-Tll3 induced an increase in cytoplasmic free calcium, the inhibitory activities of UMCD2 were not accompanied by effects on calcium fluxes. A panel of previously characterized CD2 mutants was then analyzed for binding of UMCD2 and other anti-CD2 monoclonals. Surprisingly, UMCD2 bound to all mutants tested, although the other anti-CD2 antibodies with specificity for the ligand-binding region of CD2 each failed to bind to one or more mutants. These data suggest that binding of antibody to a particular CD2 epitope can have opposite effects on the state of T cell activation, depending on the costimulus. Moreover, inhibitory effects mediated through CD2 may use a signaling mechanism distinct from that used in CD2 pathway activation. Of particular interest, the portion of the CD2 ligand-binding region recognized by UMCD2 is distinct from areas of the CD2 molecule that have previously been studied.
Kozarsky
K F
KF
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0358.
Tsai
C
C
Bott
C M
CM
Allada
G
G
Li
L L
LL
Fox
D A
DA
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis / Q000276:immunology*; D001665:Binding Sites; D018801:CD2 Antigens; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D009154:Mutation; D011971:Receptors, Immunologic / Q000032:analysis / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D011971:Receptors, Immunologic; D002118:Calcium