Stimulation of tumor-draining lymph node cells with superantigenic staphylococcal toxins leads to the generation of tumor-specific effector T cells.
In animal studies, lymph nodes (LN) draining progressive tumors contain immunologically sensitized but functionally deficient T cells. These preeffector cells can differentiate into mature effector cells on stimulation in vitro with anti-CD3 and IL-2. However, anti-CD3 react with all T cells and the activated cell population expressed a broad but normal distribution of V beta phenotypes. In this study, we examined the feasibility of using bacterial superantigens to stimulate tumor-draining LN cells. Because of their TCR V beta restriction, superantigen activation may afford a means to identify T cell subsets that are important in the antitumor immune response. Stimulation of draining LN cells with staphylococcal enterotoxins A (SEA) or B (SEB) followed by culture in IL-2 resulted in selective activation and expansion of V beta 3 and V beta 11 or V beta 3 and V beta 8 T cells, respectively. However, in adoptive immunotherapy, SEB- but not SEA-activated cells mediated the regression of established pulmonary metastases. To define the relative antitumor effects of V beta 3 and V beta 8 T cells, SEB-activated cells were depleted of either V beta 3 or V beta 8 T cells with mAb and magnetic beads. The antitumor effects were demonstratably diminished after V beta 8 cell depletion but enhanced after V beta 3 cell depletion. Using antigenically distinct MCA 205 and 207 sarcomas, tumor regression mediated by the activated cells was found to be immunologically specific for the tumor that stimulated the draining LN. Furthermore, the SEB-activated cells were virtually all T cells consisting of approximately equal proportions of CD4+ and CD8+ cells and the collaboration of the two T cell subsets was required for in vivo antitumor effects. However, the helper function of CD4+ cells could be facilitated by the administration of exogenous IL-2. Despite their in vivo antitumor reactivity, SEB-activated cells did not exhibit tumor cytotoxicity in the 4-h 51Cr release assay. However, they secreted IFN-gamma on specific stimulation with tumor cells. Taken together, these results provide for the first time clear evidence of the functional significance of superantigen interactions with immunologically committed T cells and suggest a preferential V beta use that might be associated with the T cell immune response to progressively growing tumors.
Shu
S
S
Department of Surgery, University of Michigan, Ann Arbor 48109.
Krinock
R A
RA
Matsumura
T
T
Sussman
J J
JJ
Fox
B A
BA
Chang
A E
AE
Terman
D S
DS
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004768:Enterotoxins / Q000276:immunology*; D005260:Female; D007116:Immunization, Passive; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D008175:Lung Neoplasms / Q000556:secondary; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000276:immunology* / Q000628:therapy; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D000942:Antigens, Bacterial; D004768:Enterotoxins; D007376:Interleukin-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma