Human leukocyte antigen class I-restricted immunosuppression by human CD8+ regulatory T cells requires CTLA-4-mediated interaction with dendritic cells.
We previously reported autoreactive CD8(+) regulatory T cells (Tregs) that were expanded and cloned from human peripheral blood by coculture with autologous dendritic cells (DC). Here we demonstrate that these CD8(+) Tregs require human leukocyte antigen (HLA)-class I restricted activation and then mediate cell-contact-dependent suppression of CD4(+) T cells. CD8(+) Tregs interacted with DC to suppress T-cell responses but DC were not irreversibly altered by this interaction because they could subsequently stimulate CD4(+) T cells normally. The ability of DC to form conjugates with CD4(+) T cells was reduced in the presence of CD8(+) Tregs. Suppression was blocked by Abs to CD80 and CTLA-4, implicating CTLA-4:CD80 interactions in the function of CD8(+) Tregs. CD8(+) Tregs rapidly express very high levels of surface CTLA-4 following activation compared with conventional T cells. Related to this, the expression of TRAT1 mRNA (T-cell receptor interacting molecule, or TRIM) was highly upregulated in microarray analysis of CD8(+) Tregs compared with conventional cytotoxic or nonregulatory CD8(+) T cells. TRIM acts to chaperone CTLA-4 transport to the cell surface; this function would be required to account for the phenotypic and functional properties of CD8(+) Tregs.
Jarvis
Lorna B
LB
Department of Rheumatology, University of Cambridge, Cambridge, UK.
Goodall
Jane C
JC
Gaston
J S Hill
JS
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000276:immunology; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D020869:Gene Expression Profiling; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D015703:Antigens, CD; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D012333:RNA, Messenger; C114030:TRAT1 protein, human