title: TGF-β prevents T follicular helper cell accumulation and B cell autoreactivity.
abstract: T follicular helper (Tfh) cells contribute to the establishment of humoral immunity by controlling the delivery of helper signals to activated B cells; however, Tfh development must be restrained, as aberrant accumulation of these cells is associated with positive selection of self-reactive germinal center B cells and autoimmunity in both humans and mice. Here, we show that TGF-β signaling in T cells prevented Tfh cell accumulation, self-reactive B cell activation, and autoantibody production. Using mice with either T cell-specific loss or constitutive activation of TGF-β signaling, we demonstrated that TGF-β signaling is required for the thymic maturation of CD44⁺CD122⁺Ly49⁺CD8⁺ regulatory T cells (Tregs), which induce Tfh apoptosis and thus regulate this cell population. Moreover, peripheral Tfh cells escaping TGF-β control were resistant to apoptosis, exhibited high levels of the antiapoptotic protein BCL2, and remained refractory to regulation by CD8+ Tregs. The unrestrained accumulation of Tfh cells in the absence of TGF-β was dependent on T cell receptor engagement and required B cells. Together, these data indicate that TGF-β signaling restrains Tfh cell accumulation and B cell-associated autoimmunity and thereby controls self-tolerance.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: McCarron
authors.forename: Julien C
authors.initials: JC
authors.lastname: Marie
mesh_terms: D000818:Animals; D017209:Apoptosis; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation; D018960:Hyaluronan Receptors / Q000378:metabolism; D007108:Immune Tolerance; D056724:Immunity, Humoral; D053646:Interleukin-2 Receptor beta Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013950:Thymus Gland / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D018960:Hyaluronan Receptors; D053646:Interleukin-2 Receptor beta Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1