Peripheral tolerance in mice expressing a liver-specific class I molecule: inactivation/deletion of a T-cell subpopulation.

Abstract

We previously demonstrated that C3H/HeJ transgenic (TG) mice that express a laboratory-engineered class I molecule, Q1O/L, exclusively on liver parenchymal cells show no evidence of hepatic disease even after deliberate immunization. Nevertheless, these animals demonstrate cytotoxic T-lymphocyte (CTL) activity specific for Q1O/L, although it is less than that obtained from non-TG littermates. We now show that this decrease in CTL activity is not a reflection of a decrease in precursors, since both TG and normal animals have similar numbers. When non-TG C3H mice are primed with H-2Ld and H-2KbmI antigens, which extensively crossreact with Q1O/L, their specific in vitro CTL activity directed against H-2Ld, H-2Kbml, and Q1O/L is increased 10-to 20-fold, as expected. Although primed TG mice show similar increases in in vitro CTL activity directed against H-2Ld and H-2Kbm'l, they display no increase in anti-Q10/L activity. Whereas anti-H-2Ld spleen cells from non-TG mice readily generate CTL lines and clones specific for H-2Ld and Q1O/L, TG cells give rise to anti-H-2Ld lines or clones only. These data indicate that the tolerance in TG mice is accounted for by the inactivation or deletion of an important CTL subpopulation having the capability of recognizing the peripheral antigen in situ. To determine whether tolerance would persist in the absence of Q1O/L, TG cells were transferred into non-TG recipients. Three weeks later Q1O/L-specific lytic activity generated in in vitro bulk cultures remained reduced compared to non-TG cells, indicating that the tolerant phenotype was stable during this interval.

Organ injury associated with extrathymic induction of immune tolerance in doubly transgenic mice.

“…The reduced alloreactivity of residual T cells from doubly transgenic mice is in agreement with studies that show a reduced T-cell responsiveness associated with peripheral expression of self-antigen (2)(3)(4)(5)(6) …”

“…4). At birth (5,6,9,11,(19)(20)(21)(22)(23)(24). Likewise, EL singly transgenic mice did not develop spontaneous autoimmunity in exocrine pan- creas.…”

“…Some investigators have reported the induction of T-cell unresponsiveness to peripherally expressed antigen (2)(3)(4)(5)(6), whereas others have found normal or near normal responsiveness (7)(8)(9)(10)(11). In those studies where functional tolerance was found, it was unclear whether autoreactive T cells were deleted or simply rendered functionally unresponsive, because it was not possible to track specific T cells in vivo.…”

Requirements and Challenges of a Preclinical Autoimmune Hepatitis Mouse Model

“…In contrast to naïve splenocytes, those that were primed and activated from nontransgenic animals caused a periportal infiltrate after transfer into Q10/H-2L d -bearing transgenic mice. The study concluded that hepatocytes expressing a neoantigen on their surface can provide antigen-specific T cell tolerance [53,54]. It is not quite clear whether tolerance induction in this model results from T cell anergy or deletion because the fate of antigen-specific T cells cannot be followed in vivo properly.…”

“…Among the first studies to use a liver-specific neoantigen were those performed by Jones-Youngblood et al [53], when the MHC I-like molecule Q10 was expressed as a fusion protein with H-2L d on the surface of hepatocytes [54]. No signs of spontaneous hepatitis were seen.…”