The BTN molecule consists of three subfamilies, BTN1, BTN2. and BTN3, and possesses interesting properties for biological regulation. Although the biological significance of BTN1 and BTN2 has been progressively clarified, the receptor function of BTN3 remains to be elucidated as a result of the absence of appropriate agonists. To clarify the participation of BTN3 in immune regulation, BTN3-specific mAb, referred to as 34-7 and 232-5, were generated from BTN3 gene-immunized mice. The 232-5 mAb, specific to the extracellular domain of the BTN3 molecule, stained almost all populations of human PBMCs, including T, NK, NKT, and B cells. Notably, treatment with the 232-5 mAb resulted in phosphorylation of BTN3A3 molecules, leading to attenuated proliferation and cytokine secretion by CD4+ and CD8+ T cells in a CD4+ CD25+ Treg cell-independent manner, demonstrating the agonistic property of the 232-5 mAb in BTN3-mediated negative signal transduction. The magnitude of the cell surface expression of BTN3 molecules correlated inversely with lymphocyte activity, suggesting that BTN3 molecules contribute to the maintenance of the immune system. Taken together, our findings provide new insights for the role of BTN3 as an inhibitor of excessive cellular immune responses.
This study demonstrates that CD4(+) T cells specific for an altered self-antigen differentiate to T cells secreting transforming growth factor (TGF)-beta1. In this study, we utilized mice expressing an altered peptide ligand containing a single amino acid substitution of moth cytochrome c 88-103 peptide. In these mice, antigen-specific T cells escaping thymic negative selection differentiated into T cells with an effector/memory phenotype, CD44(high), CD45RB(low), CD62L(-) and CD25(intermediate). The expression of CD25 and high levels of CD44 was initiated in the thymus during the development from CD4(+)CD8(+) to CD4(+); a large proportion of maturing CD4(+) thymocytes expressed both CD25 and high levels of CD44. Upon antigen stimulation, CD4(+) T cells derived from these mice did not proliferate or secrete IL-2, but secreted TGF-beta1. Neutralizing antibodies to TGF-beta1 reversed the impaired proliferative responses to the antigen, suggesting that TGF-beta1 secreted from these T cells negatively regulates T cell responses.
Aggressive immunity characterized by the motion of cytotoxic T lymphocytes (CTLs), T helper (Th) 1 cells, and natural killer (NK) cells is the first line of defense against intracellular microorganism invasion and tumor formation. In patients with infectious diseases and tumors, aggressive immunity is often attenuated by immune suppressive effects provided by regulatory T (Treg) cells including CD4(+) CD25(+) forkhead-box (fox) p3(+) T cells, T regulatory (Tr) 1, Th3, and a subpopulation of gammadelta-type of T cell receptor-expressing T (gammadelta T) cells. It has been demonstrated that Treg cells down-regulate aggressive immunity by direct cell interactions and suppressive cytokines (e.g., interleukin (IL)-10, transforming growth factor (TGF)-beta). Today, instead of synthesizing chemical agents with serious side effects, protein agents, catalytic oligonucleotides, and natural medicines involved in the elimination of Treg cell-mediated suppressive responses for the restoration of aggressive immunity are expected to be alternatives as a mild clinical remedy against microorganism invasion and tumors.
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