Editors' ChoiceImmunology

Suppressing Autoimmune Responses Through B7

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Science's STKE  20 Jul 2004:
Vol. 2004, Issue 242, pp. tw258-TW258
DOI: 10.1126/scisignal.2422004tw258

CD4+CD25+ regulatory T cells (Treg) play a key role in suppressing autoimmune activity. Their ability in vitro to inhibit the proliferation of other lymphocytes depends on direct contact; however, the underlying mechanisms are unclear. Noting that the B7 transmembrane proteins, which are expressed on antigen-presenting cells (APCs) and provide costimulatory signals to T cells, are also expressed on activated T cells, Paust et al. investigated their role in Treg-mediated suppression. Treg cells failed to suppress in vitro proliferation of activated CD4+CD25 T helper (Th) cells isolated from mice lacking B7 (B7-deficient Th), regardless of the presence of B7 on APCs. Proliferation of Th cells lacking B7-1 (CD80) or B7-2 (CD86) was partly resistant to Treg, whereas that of cells lacking both was fully resistant. Wild-type Th cells or B7-deficient Th cells transferred to RAG-2 (recombination activating gene-2-deficient) mice (which lack lymphocytes) promoted autoimmune gastritis and colitis. However, the mice that received B7-deficient Th cells also developed lethal wasting, and unlike mice that received wild-type Th cells, Treg did not suppress their autoimmune symptoms. In vitro susceptibility of B7-deficient Th to Treg suppression was restored by viral infection of the Th cells with B7-1. Full-length B7-1 or B7-2, but not mutants consisting of the B7-1 or B7-2 extracellular domains anchored with the glycosophosphatidylinositol (GPI) signal sequence (which retained costimulatory activity when expressed in APCs), conferred sensitivity to Treg suppression of B7-deficient Th cell proliferation after adoptive transfer to RAG-2 mice. Thus, B7 appears to mediate Treg suppression of Th cells, through outside-in signaling that requires the transmembrane or cytoplasmic domains.

S. Paust, L. Lu, N. McCarty, H. Cantor, Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc. Natl. Acad. Sci. U.S.A. 101, 10398-10403 (2004). [Abstract] [Full Text]

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