ICOS expression by effector T cells influences the ability of regulatory T cells to inhibit anti-chromatin B cell responses in recipient mice.
T regulatory cells are critical for the prevention of autoimmunity. Specifically, Treg cells can control anti-chromatin antibody production in vivo, and this correlates with decreased ICOS expression on CD4(+) T helper cells. Here we test the significance of high ICOS expression by T effector cells, firstly in terms of the anti-chromatin B cell response, and secondly on the ability of Treg cells to suppress T cell help. We bred CD4(+) T cell receptor transgenic mice with mice that carry the Roquin(san/san) mutation. The Roquin gene functions to limit ICOS mRNA such that CD4 T cells from mutant mice express elevated ICOS. Using an in vivo model, TS1.Roquin(san/san) Th cells were compared with wild-type TS1 Th cells with regard to their ability to help anti-chromatin B cells in the presence or absence of Treg cells. Both TS1 and TS1.Roquin(san/san) Th cells induced anti-chromatin IgM(a) antibodies, but the TS1.Roquin(san/san) Th cells resulted in the recovery of more class-switched and germinal center B cells. Neither source of Th cells were capable of inducing long-lived autoantibodies. Treg cells completely suppressed anti-chromatin IgM(a) antibody production and reduced anti-chromatin B cell recovery induced by TS1 Th cells. Importantly, this suppression was less effective when TS1.Roquin(san/san) Th cells were used. Thus, high ICOS levels on effector T cells results in autoimmunity by augmenting the autoreactive B cell response and by dampening the effect of Treg cell suppression.
Hondowicz
Brian D
BD
The Wistar Institute, Room 270, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Batheja
Amrita O
AO
Metzgar
Michele H
MH
Caton
Andrew J
AJ
Erikson
Jan
J
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000502:physiology*; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002843:Chromatin / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein; D051379:Mice; D008807:Mice, Inbred BALB C; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D000945:Antigens, Differentiation, T-Lymphocyte; D001323:Autoantibodies; D002843:Chromatin; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases