Cutting edge: Self-antigen controls the balance between effector and regulatory T cells in peripheral tissues.
Immune homeostasis in peripheral tissues is achieved by maintaining a balance between pathogenic effector T cells (Teffs) and protective Foxp3(+) regulatory T cells (Tregs). Using a mouse model of an inducible tissue Ag, we demonstrate that Ag persistence is a major determinant of the relative frequencies of Teffs and Tregs. Encounter of transferred naive CD4(+) T cells with transiently expressed tissue Ag leads to generation of cytokine-producing Teffs and peripheral Tregs. Persistent expression of Ag, a mimic of self-antigen, leads to functional inactivation and loss of the Teffs with preservation of Tregs in the target tissue. The inactivation of Teffs by persistent Ag is associated with reduced ERK phosphorylation, whereas Tregs show less reduction in ERK phosphorylation and are relatively resistant to ERK inhibition. Our studies reveal a crucial role for Ag in maintaining appropriate ratios of Ag-specific Teffs to Tregs in tissues.
Department of Dermatology, University of California San Francisco, San Francisco, CA 94143;
Iris K
IK
Gratz
Michael D
MD
Rosenblum
Megan M
MM
Maurano
Jonathan S
JS
Paw
Hong-An
HA
Truong
Ann
A
Marshak-Rothstein
Abul K
AK
Abbas
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D001549:Benzamides / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin; D010766:Phosphorylation; D012867:Skin / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation
D001324:Autoantigens; D001549:Benzamides; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17; D007376:Interleukin-2; D007371:Interferon-gamma; C506614:mirdametinib; D010047:Ovalbumin; D004159:Diphenylamine; D048049:Extracellular Signal-Regulated MAP Kinases