title: Basis of CTLA-4 function in regulatory and conventional CD4(+) T cells.
abstract: CTLA-4 proteins contribute to the suppressor function of regulatory T cells (Tregs), but the mechanism by which they do so remains incompletely understood. In the present study, we assessed CTLA-4 protein function in both Tregs and conventional (Tconv) CD4(+) T cells. We report that CTLA-4 proteins are responsible for all 3 characteristic Treg functions of suppression, TCR hyposignaling, and anergy. However, Treg suppression and anergy only required the external domain of CTLA-4, whereas TCR hyposignaling required its internal domain. Surprisingly, TCR hyposignaling was neither required for Treg suppression nor anergy because costimulatory blockade by the external domain of CTLA-4 was sufficient for both functions. We also report that CTLA-4 proteins were localized in Tregs in submembrane vesicles that rapidly recycled to/from the cell surface, whereas CTLA-4 proteins in naive Tconv cells were retained in Golgi vesicles away from the cell membrane and had no effect on Tconv cell function. However, TCR signaling of Tconv cells released CTLA-4 proteins from Golgi retention and caused activated Tconv cells to acquire suppressor function. Therefore, the results of this study demonstrate the importance of intracellular localization for CTLA-4 protein function and reveal that CTLA-4 protein externalization imparts suppressor function to both regulatory and conventional CD4(+) T cells.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Tai
authors.forename: François
authors.initials: F
authors.lastname: Van Laethem
authors.forename: Leonid
authors.initials: L
authors.lastname: Pobezinsky
authors.forename: Terry
authors.initials: T
authors.lastname: Guinter
authors.forename: Susan O
authors.initials: SO
authors.lastname: Sharrow
authors.forename: Anthony
authors.initials: A
authors.lastname: Adams
authors.forename: Larry
authors.initials: L
authors.lastname: Granger
authors.forename: Michael
authors.initials: M
authors.lastname: Kruhlak
authors.forename: Tullia
authors.initials: T
authors.lastname: Lindsten
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Alfred
authors.initials: A
authors.lastname: Singer
mesh_terms: D000818:Animals; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology*; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology*; D017635:Clonal Anergy / Q000502:physiology*; D006056:Golgi Apparatus / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D011948:Receptors, Antigen, T-Cell