CD8+CD122+CD49dlow regulatory T cells maintain T-cell homeostasis by killing activated T cells via Fas/FasL-mediated cytotoxicity

Significance Our study demonstrated that CD8+CD122+CD49dlow regulatory T cells induced apoptosis in target T cells depending on death receptor Fas (CD95)–FasL (CD178) interaction. This in vitro phenomenon reflected the regulatory activity of these cells in vivo, which was also reproducible in the in vivo experimental system of adoptive T-cell transfer. By using natural mutant mice of Fas or FasL and the gene-targeted mice of IL-10, we confirmed that the regulatory activity of CD8+CD122+CD49dlow cells was mediated by Fas–FasL but not by IL-10. In addition, the necessity of MHC class I molecules on the target T cells was also confirmed by analysis using CD8+ T cells that lack β2-microglobulin and consequently class I MHC. The Fas/FasL (CD95/CD178) system is required for immune regulation; however, it is unclear in which cells, when, and where Fas/FasL molecules act in the immune system. We found that CD8+CD122+ cells, which are mostly composed of memory T cells in comparison with naïve cells in the CD8+CD122− population, were previously shown to include cells with regulatory activity and could be separated into CD49dlow cells and CD49dhigh cells. We established in vitro and in vivo experimental systems to evaluate the regulatory activity of CD122+ cells. Regulatory activity was observed in CD8+CD122+CD49dlow but not in CD8+CD122+CD49dhigh cells, indicating that the regulatory cells in the CD8+CD122+ population could be narrowed down to CD49dlow cells. CD8+CD122− cells taken from lymphoproliferation (lpr) mice were resistant to regulation by normal CD122+ Tregs. CD122+ Tregs taken from generalized lymphoproliferative disease (gld) mice did not regulate wild-type CD8+CD122− cells, indicating that the regulation by CD122+ Tregs is Fas/FasL-dependent. CD122+ Tregs taken from IL-10–deficient mice could regulate CD8+CD122− cells as equally as wild-type CD122+ Tregs both in vitro and in vivo. MHC class I-missing T cells were not regulated by CD122+ Tregs in vitro. CD122+ Tregs also regulated CD4+ cells in a Fas/FasL-dependent manner in vitro. These results suggest an essential role of Fas/FasL as a terminal effector of the CD122+ Tregs that kill activated T cells to maintain immune homeostasis.

[1]  T. Holderried,et al.  Stable inhibitory activity of regulatory T cells requires the transcription factor Helios , 2015, Science.

[2]  C. Riccardi,et al.  Role of caspase-8 in thymus function , 2013, Cell Death and Differentiation.

[3]  Y. Okuno,et al.  CD8+ CD122+ regulatory T cells contain clonally expanded cells with identical CDR3 sequences of the T‐cell receptor β‐chain , 2013, Immunology.

[4]  Xuetao Cao,et al.  CD11chighCD8+ Regulatory T Cell Feedback Inhibits CD4 T Cell Immune Response via Fas Ligand–Fas Pathway , 2013, The Journal of Immunology.

[5]  Sangsik Lee,et al.  The roles of FADD in extrinsic apoptosis and necroptosis. , 2012, BMB reports.

[6]  D. Roopenian,et al.  CD8+ T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice , 2011, Proceedings of the National Academy of Sciences.

[7]  Y. Okuno,et al.  CD8+CD122+ Regulatory T Cells (Tregs) and CD4+ Tregs Cooperatively Prevent and Cure CD4+ Cell-Induced Colitis , 2011, The Journal of Immunology.

[8]  Tara Beeston,et al.  Involvement of IFN-γ and perforin, but not Fas/FasL interactions in regulatory T cell-mediated suppression of experimental autoimmune encephalomyelitis , 2010, Journal of Neuroimmunology.

[9]  H. Dai,et al.  Cutting Edge: Programmed Death-1 Defines CD8+CD122+ T Cells as Regulatory versus Memory T Cells , 2010, The Journal of Immunology.

[10]  Zhe Shi,et al.  Human CD8+CXCR3+ T cells have the same function as murine CD8+CD122+ Treg , 2009, European journal of immunology.

[11]  A. Strasser,et al.  The many roles of FAS receptor signaling in the immune system. , 2009, Immunity.

[12]  T. Whiteside,et al.  Human Circulating CD4+CD25highFoxp3+ Regulatory T Cells Kill Autologous CD8+ but Not CD4+ Responder Cells by Fas-Mediated Apoptosis1 , 2009, The Journal of Immunology.

[13]  M. Kopf,et al.  SCART Scavenger Receptors Identify a Novel Subset of Adult γδ T Cells1 , 2008, The Journal of Immunology.

[14]  K. Isobe,et al.  CD8+CD122+ regulatory T cells recognize activated T cells via conventional MHC class I-alphabetaTCR interaction and become IL-10-producing active regulatory cells. , 2008, International immunology.

[15]  Vipin Kumar,et al.  Revival of CD8+ Treg-mediated suppression. , 2008, Trends in immunology.

[16]  K. Isobe,et al.  Importance of CD80/CD86–CD28 interactions in the recognition of target cells by CD8+CD122+ regulatory T cells , 2008, Immunology.

[17]  K. Isobe,et al.  Essential Role of CD8+CD122+ Regulatory T Cells in the Recovery from Experimental Autoimmune Encephalomyelitis1 , 2008, The Journal of Immunology.

[18]  S. Sakaguchi,et al.  Regulatory T cells – a brief history and perspective , 2007, European journal of immunology.

[19]  Shimon Sakaguchi,et al.  Natural regulatory T cells: mechanisms of suppression. , 2007, Trends in molecular medicine.

[20]  W. Powell,et al.  Human CD4+CD25+ Regulatory T Lymphocytes Inhibit Lipopolysaccharide-Induced Monocyte Survival through a Fas/Fas Ligand-Dependent Mechanism1 , 2006, The Journal of Immunology.

[21]  Shimon Sakaguchi,et al.  Foxp3+CD25+CD4+ natural regulatory T cells in dominant self‐tolerance and autoimmune disease , 2006, Immunological reviews.

[22]  J. Sprent,et al.  A major histocompatibility complex class I–dependent subset of memory phenotype CD8+ cells , 2006, The Journal of experimental medicine.

[23]  K. Isobe,et al.  Cutting Edge: CD8+CD122+ Regulatory T Cells Produce IL-10 to Suppress IFN-γ Production and Proliferation of CD8+ T Cells1 , 2005, The Journal of Immunology.

[24]  Y. Kawamoto,et al.  Essential Roles of CD8+CD122+ Regulatory T Cells in the Maintenance of T Cell Homeostasis , 2004, The Journal of experimental medicine.

[25]  M. Shinohara,et al.  Analysis of regulatory CD8 T cells in Qa-1-deficient mice , 2004, Nature Immunology.

[26]  Stephen G. Lisberger,et al.  Models of Cerebellar Function , 2002 .

[27]  N. Suciu-Foca,et al.  CD8+ T suppressor cells are back to the game: are they players in autoimmunity? , 2002, Autoimmunity reviews.

[28]  A. Galluzzo,et al.  Regulation of Apoptosis in Endocrine Autoimmunity , 2002 .

[29]  B. Graham,et al.  IL-4 Diminishes Perforin-Mediated and Increases Fas Ligand-Mediated Cytotoxicity In Vivo1 , 2000, The Journal of Immunology.

[30]  Yan Zhou,et al.  Normal Regulatory α/β T Cells Effectively Eliminate Abnormally Activated T Cells Lacking the Interleukin 2 Receptor β in Vivo , 1999, The Journal of experimental medicine.

[31]  Yan Zhou,et al.  Normal regulatory alpha/beta T cells effectively eliminate abnormally activated T cells lacking the interleukin 2 receptor beta in vivo. , 1999 .

[32]  N. Sarvetnick,et al.  Comparing the relative role of perforin/granzyme versus Fas/Fas ligand cytotoxic pathways in CD8+ T cell-mediated insulin-dependent diabetes mellitus. , 1999, Journal of immunology.

[33]  S. Nagata,et al.  Why do defects in the Fas-Fas ligand system cause autoimmunity? , 1997, The Journal of allergy and clinical immunology.

[34]  H. Griesser,et al.  Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. , 1995, Science.

[35]  N. Ishimaru,et al.  Mechanism of activation-induced cell death of T cells and regulation of FasL expression. , 2014, Critical reviews in immunology.

[36]  S. Sakaguchi.  Regulatory T cells: history and perspective. , 2011, Methods in molecular biology.

[37]  M. Kopf,et al.  SCART scavenger receptors identify a novel subset of adult gammadelta T cells. , 2008, Journal of immunology.

[38]  A. Galluzzo,et al.  Regulation of apoptosis in endocrine autoimmunity: insights from Hashimoto's thyroiditis and Graves' disease. , 2002, Annals of the New York Academy of Sciences.

[39]  S. Nagata,et al.  Fas and Fas ligand: lpr and gld mutations. , 1995, Immunology today.

[40]  E. Sercarz,et al.  Specificity and interactions of CD8+ T suppressor cells. , 1989, Research in immunology.