title: TGF-beta signaling regulates CD8+ T cell responses to high- and low-affinity TCR interactions.
abstract: Absence of transforming growth factor-beta (TGF-beta) signaling to T cells in mice results in an increase in T cell numbers, an activated CD44 high, CD69-, CD25- T cell phenotype and a T cell-mediated injury to many organs. It is not known if such T cell activation in the absence of TGF-beta signaling is spontaneous or due to aberrant T cell responses to a physiological stimulus. We used adoptive transfer of CD8+ T cells from mice double transgenic for the OT-1 TCR and the TGF-beta1-dominant negative transgene [OT-dominant-negative receptor (DNR)] to investigate the role of TGF-beta in regulating CD8+ T cell activation in vivo. The activation and expansion of single-transgenic OT and double-transgenic OT-DNR cells to oral antigens, high-affinity and low-affinity peptides were indistinguishable. Activation with high-affinity peptide and CFA however resulted in greater expansion of OT-DNR cells in comparison to OT cells. Low-affinity peptide and adjuvant did not result in OT cell activation or expansion but results in up-regulation of CD44 on OT-DNR cells. These data show that TGF-beta functions in vivo to limit the scale of CD8+ T cell expansion after high-affinity peptide-MHC interactions. TGF-beta also limits T cell activation to the highest affinity peptide-MHC interactions. The increase in T cell number and activation present in TGF-beta-deficient and TGF-beta DNR-expressing mice may be due to the loss of these two phenomena.
authors.affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. wajahat.mehal@yale.edu
authors.forename: Wajahat Z
authors.initials: WZ
authors.lastname: Mehal
authors.forename: Shehzad Z
authors.initials: SZ
authors.lastname: Sheikh
authors.forename: Leonid
authors.initials: L
authors.lastname: Gorelik
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D000941:Antigens / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D015703:Antigens, CD; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta