Identification of a novel natural regulatory CD8 T-cell subset and analysis of its mechanism of regulation.
The immune system contains natural regulatory T cells that control the magnitude of the immune response during physiologic and pathologic conditions. Although this suppressive function was historically attributed to CD8 T cells, most recent reports have focused on natural regulatory CD4 T cells. In the present study, we describe a new subset of natural CD8 regulatory T cells in normal healthy animals. This subset expresses low levels of CD45RC at its surface (CD45RC(low)); produces mainly interleukin-4 (IL-4), IL-10, and IL-13 cytokines upon in vitro stimulation; expresses Foxp3 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4); and is not cytotoxic against allogeneic targets. This subset suppresses the proliferation and differentiation of autologous CD4 T cells into type-1 cytokines producing T cells after stimulation with allogeneic accessory cells. We also provide evidence that this regulatory subset mediates its suppression by cell-to-cell contact and not through secretion of suppressive cytokines. Finally, the regulatory activity of CD8 CD45RC(low) cells is also demonstrated in vivo in a rat model of CD4-dependent graft-versus-host disease. Collectively, these data demonstrate for the first time that freshly isolated rat CD8 CD45RC(low) T cells contain T cells with regulatory properties, a result that enlarges the general picture of T-cell-mediated regulation.
Institut National de la Santé et de la Recherche Médicale U563, Hôpital Purpan and Université Paul Sabatier, Toulouse, France.
Emmanuel
E
Xystrakis
Anne S
AS
Dejean
Isabelle
I
Bernard
Philippe
P
Druet
Roland
R
Liblau
Daniel
D
Gonzalez-Dunia
Abdelhadi
A
Saoudi
D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000145:classification / Q000166:cytology* / Q000378:metabolism*; D060908:CTLA-4 Antigen; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D008297:Male; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016176:T-Lymphocyte Subsets / Q000145:classification / Q000166:cytology*; D014184:Transplantation, Homologous
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015415:Biomarkers; D060908:CTLA-4 Antigen; C556708:Ctla4 protein, rat; D016207:Cytokines; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1