title: Construction of self-recognizing regulatory T cells from conventional T cells by controlling CTLA-4 and IL-2 expression.
abstract: Thymus-produced CD4(+) regulatory T (Treg) cells, which specifically express the transcription factor forkhead box p3, are potently immunosuppressive and characteristically possess a self-reactive T-cell receptor (TCR) repertoire. To determine the molecular basis of Treg suppressive activity and their self-skewed TCR repertoire formation, we attempted to reconstruct these Treg-specific properties in conventional T (Tconv) cells by genetic manipulation. We show that Tconv cells rendered IL-2 deficient and constitutively expressing transgenic cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) were potently suppressive in vitro when they were preactivated by antigenic stimulation. They also suppressed in vivo inflammatory bowel disease and systemic autoimmunity/inflammation produced by Treg deficiency. In addition, in the thymus, transgenic CTLA-4 expression in developing Tconv cells skewed their TCR repertoire toward higher self-reactivity, whereas CTLA-4 deficiency specifically in developing thymic Treg cells cancelled their physiological TCR self-skewing. The extracellular portion of CTLA-4 was sufficient for the suppression and repertoire shifting. It interfered with CD28 signaling to responder Tconv cells via outcompeting CD28 for binding to CD80 and CD86,or modulating CD80/CD86 expression on antigen-presenting cells. Thus, a triad of IL-2 repression, CTLA-4 expression, and antigenic stimulation is a minimalistic requirement for conferring Treg-like suppressive activity on Tconv cells, in accordance with the function of forkhead box p3 to strongly repress IL-2 and maintain CTLA-4 expression in natural Treg cells. Moreover, CTLA-4 expression is a key element for the formation of a self-reactive TCR repertoire in natural Treg cells. These findings can be exploited to control immune responses by targeting IL-2 and CTLA-4 in Treg and Tconv cells.
authors.affiliation: Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kishi
authors.forename: Motonao
authors.initials: M
authors.lastname: Osaki
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Morikawa
authors.forename: Paz
authors.initials: P
authors.lastname: Prieto-Martin
authors.forename: Kajsa
authors.initials: K
authors.lastname: Wing
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D001667:Binding, Competitive; D018106:CD28 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D003713:Dendritic Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007111:Immunity, Cellular / Q000276:immunology*; D015212:Inflammatory Bowel Diseases / Q000276:immunology; D007376:Interleukin-2 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D007376:Interleukin-2
keywords: CD25; immune tolerance; thymic selection