Type 1 versus type 2 cytokine release by Vbeta T cell subpopulations determines in vivo antitumor reactivity: IL-10 mediates a suppressive role.
We have previously reported that CD8+ tumor-draining lymph node (TDLN) cells activated with anti-CD3 and IL-2-mediated tumor regression in adoptive immunotherapy. In this study, we examined the TCR Vbeta repertoire usage of TDLN cells with respect to cytokine release profiles and therapeutic efficacy in vivo. The majority of the whole population of TDLN cells after activation with anti-CD3 were composed of Vbeta3+, -5+, -7+, -8+, and -11+ cells. Enrichment of Vbeta subsets of TDLN cells by in vitro activation with anti-Vbeta mAb revealed Vbeta8+ cells released high amounts of IFN-gamma and granulocyte/macrophage-CSF (GM-CSF) with minimal amounts of IL-10 in response to tumor and mediated tumor regression in vivo. In contrast, enriched populations of Vbeta5+, Vbeta7+, and Vbeta11+ cells released low amounts of IFN-gamma and GM-CSF with high levels of IL-10 and had no in vivo antitumor reactivity. In vitro depletion of specific Vbeta subsets from the whole TDLN pool confirmed that the profile of cytokines released correlated with in vivo antitumor function. Therapeutic efficacy mediated by TDLN cells required the release of IFN-gamma and GM-CSF since in vivo neutralization of both cytokines inhibited tumor regression. The administration of anti-IL-10 mAb abrogated the suppressed antitumor response manifested by adoptively transferred TDLN cells, which elaborated increased levels of IL-10. Our study documents that type 1 cytokine release (i.e., IFN-gamma and GM-CSF) promotes in vivo tumor Ag recognition, in contrast to type 2 release (i.e., IL-10), which suppresses this interaction, and discriminates the functional activity of Vbeta subpopulations of effector cells.
Aruga
A
A
Department of Surgery, University of Michigan, Ann Arbor 48109, USA.
Aruga
E
E
Tanigawa
K
K
Bishop
D K
DK
Sondak
V K
VK
Chang
A E
AE
D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D005260:Female; D007135:Immunoglobulin Variable Region / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D000951:Antigens, Neoplasm; D016207:Cytokines; D007135:Immunoglobulin Variable Region; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016753:Interleukin-10