Cell-intrinsic and -extrinsic control of Treg-cell homeostasis and function revealed by induced CD28 deletion.
While the requirement for CD28 and its ligands for the generation and function of "natural" (n)Treg cells is well established, it has not been possible yet to investigate cell-intrinsic effects after interrupted CD28 expression. Here, we demonstrate a selective loss of Treg cells after disruption of the CD28 gene. The decline in Treg-cell number was accompanied by reduced homeostatic proliferation, probably due to lack of costimulation during self-antigen recognition, and by impaired Treg-cell function including downregulation of CTLA-4. The decline in Treg-cell number was unaffected by thymectomy or by the presence of CD28 expressing T cells within the same animal, indicating that impairment of peripheral homeostasis and function of nTreg cells by CD28 deletion is cell-intrinsic. In contrast, downregulation of CD25, the α chain of the IL-2R, did not occur in the presence of WT T cells, indicating that its expression does not depend on CD28 signals in cis.
Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
Tea
T
Gogishvili
Fred
F
Lühder
Sandra
S
Goebbels
Sandra
S
Beer-Hammer
Klaus
K
Pfeffer
Thomas
T
Hünig
D019264:Adoptive Transfer; D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D006706:Homeostasis; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D053645:Interleukin-2 Receptor alpha Subunit