Activation and preferential expansion of rat cytotoxic (CD8) T cells in vitro and in vivo with a bispecific (anti-TCR alpha/beta x anti-CD2) F(ab')2 antibody.
We show that a bispecific F(ab')2 Ab (BsAb), which cross-links the TCR to CD2 ([anti-CD2 x anti-TCR]) and is highly mitogenic in vitro, also induces marked T cell activation and proliferation when given as a small single dose (50 to 100 micrograms) to rats. Interestingly, the proliferation appeared selective for CD8 cells, increasing this compartment more than 20 times over 72 h. This resulted in a three- to fourfold increase in spleen weight, with histologic evidence of T-zone and red pulp expansion by CD8+ blast cells. Such changes were in striking contrast to those seen after a similar amount of the parent IgG anti-TCR mAb, R73, which, while inducing a transient increase in CD25+ cells, failed to alter the lymphocyte composition. The mitogenic activity of the BsAb was totally dependent on its ability to cross-link CD2 and the TCR, hence a mixture of anti-CD2 and anti-TCR F(ab')2 fragments was without effect in vitro or in vivo. Unlike normal rat T cells or those taken from R73 IgG-treated rats, blood and splenic T cells recovered from BsAb-treated rats were highly cytotoxic against R73 hybridoma targets that express surface anti-TCR mAb and consequently trigger the lytic activity of activated CTL or a rat lymphoma line, LAMA (Thy-1+), using a second BsAb, [anti-TCR x anti-Thy-1], to retarget the CTL. This latter assay provides the basis for a future two-stage targeting strategy for cancer immunotherapy in which a mitogenic BsAb would be given to patients to activate CTL nonspecifically, and then, at an appropriate time, a second BsAb [anti-TCR x antitumor] would be given to deliver activated cells to the tumor target cells.
Tutt
A L
AL
Lymphoma Research Unit, General Hospital, Southampton, United Kingdom.
Reid
R
R
Wilkins
B S
BS
Glennie
M J
MJ
D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000276:immunology*; D018801:CD2 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002455:Cell Division; D002478:Cells, Cultured; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051381:Rats; D011914:Rats, Inbred BN; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology
D018033:Antibodies, Bispecific; D018801:CD2 Antigens; D007140:Immunoglobulin Fab Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta